This invention relates to the field of prodrugs, that is novel derivatives of otherwise known and proven drugs which release that drug in active or pro-active form in vivo. The enzymatic and/or chemical cleavage of the compounds of the present invention occurs in such a manner that the parent drug is released and the moiety or moieties split off remain non-toxic or are metabolized so that non-toxic or acceptable amounts of metabolic products are produced. The present compounds thus modify the in vivo availability of the parent compound compared to what would be the case if the parent compound was to be administered itself. For instance the prodrugs of the invention may give higher bioavailabities, varied bioavailability kinetics or bioavailabilities with a decreased interpersonal spread.
A first aspect of the invention relates to the field of nucleoside analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the DNA polymerase of Hepatitis B Virus (HBV). The invention provides novel compounds with favourable pharmaceutical parameters, methods for their preparation, pharmaceutical compositions comprising these compounds and methods employing then for the inhibition of viral and neoplastic diseases including HBV and HIV.
International patent application no. WO 88/00050 describes the antiretroviral and anti-HBV activity of a series of 3xe2x80x2-fluorinated nucleosides, including the compounds 2xe2x80x2, 3xe2x80x2-dideoxy, 3xe2x80x2-fluoroguanosine (LG) and 3xe2x80x2-fluorothymidine FLT). The latter compound underwent clinical evaluation as an anti-mECV agent and although its antiviral activity and pharmacokinetics were good, it showed unexpected toxicity (Flexner et al, J Inf Dis 170(6) 1394-403 (1994)). The former compound FLG is very active in vitro however the present inventors have detected that its bioavailability is so poorxe2x80x94around 4%xe2x80x94that the in vivo utility of the compound has thus far been limited to intraperitoneally or subcutaneously administered animal models. U.S. Pat. No. 4,963,662 discloses generically a series of 3xe2x80x2-fluorinated nucleosides and corresponding triphosphates and specifically describes the preparation of the 5xe2x80x2-O-palmitoyl derivative of FLT, without reporting any improvement in bioavailability. International patent application WO 93 13778 describes FLG derivatives modified at the 6-position of the base, in particular with n-propoxy, cyclobutoxy, cyclopropylamino, piperidino or pyrrolidino. International patent application no. 93 14103 describes FLG derivatives where the oxygen at the guanine 6-position is replaced with amino, ether, halo or sulphonate.
In accordance with one aspect of the invention there are provided compounds of the formula I 
wherein:
R1 is selected from
hydroxy, amino or carboxy; optionally having esterified/amide bonded thereon a C4-C22 saturated or unsaturated, optionally substituted fatty acid or alcohol or an aliphatic L-amino acid;
R2 is the residue of an aliphatic L-amino acid;
L1 is a trifunctional linker group;
L2 is absent or a difunctional linker group,
and pharmaceutically acceptable salts thereof.
The invention further provides pharmaceutical compositions comprising the compounds and salts of formula I and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HBV and retroviruses such as HIV, comprising bringing a compound or salt of the formula I into contact with a retrovirus or HBV, for example by administering an effective amount of the compound or salt to an individual afflicted with a retrovirus or HBV. The invention also extends to the use of the compounds or salts of formula I in therapy, for example in the preparation of a medicament for the treatment of retroviral or HBV infections.
In treating conditions caused by retroviruses such as HIV, or HBV, the compounds or salts of formula I are preferably administered in an amount of 50 to 1 500 mg once, twice or three times per day, especially 100 to 700 mg twice or thrice daily. It is desirable to achieve serum levels of the active metabolite of 0.01 to 100 xcexcg/ml, especially 0.1 to 5 xcexcg/ml.
Where R1 is a fatty acid residue, it preferably has in total an even number of carbon atoms, advantageously decanoyl (C10), lauryl (C12), myristoyl (C14), palmitoyl (C16), stearoyl (C18), eicosanoyl (C20) or behenoyl (C22). The fatty acid preferably has in total 10 to 22, and more preferably 16 to 20 carbon atoms, especially 18. The fatty acid may be unsaturated and have one to three double bonds, especially one double bond. Unsaturated fatty acids preferably belong to the n-3 or n-6 series. Convenient unsaturated R1 groups include those derived from the monounsaturated acids myristoleic, myristelaidic, palmitoleic, palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic, brassidic acids or multiply unsaturated fatty acids such as linoleic, xcex3-linolenic, arachidonic acid and xcex1-linolenic acid. Preferably, however, R1 as a fatty acid is saturated as these compounds tend to have superior stability and shelf life.
R1 as fatty alcohol residue preferably corresponds to one of the above described fatty acids. Alternatively the fatty alcohol may comprise residues of shorter alcohols, such as methanol ethanol or propanol.
R1 as a saturated or unsaturated fatty acid or alcohol may optionally be substituted with up to five similar or different substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro, and the like.
Suitable aliphatic amino acids for R2 and, if present R1, include L-alanine, L-leucine, L-isoleucine and most preferably L-valine. For ease of synthesis it is preferred that both R2 and R1 are residues of aliphatic amino acids, preferably the same residue.
The expression trifunctional in the context of the first linker group L1 means that the linker has at least three functional groups, including at least two functional groups derived from respective hydroxy, amine or carboxyl groups, the amine and hydroxy function(s) being available for esterification/amide bonding with the carboxy functions of R1 and R2 whereas a carboxy function(s) on the linker is available for amide bonding with the free xcex1-amine function of R2, or R1 as the case may be, or esterification with R1 as a fatty alcohol. Where R1 itself defines an hydroxy, amide or carboxy group, the hydroxy group being presently favoured of the three, one of said functions on the trifunctional linker simply comprises this hydroxy, amide or carboxy group.
The trifunctional linker further comprises a third functional group for linkage with either the optional second linker group L2 illustrated in more detail below, or the hydroxy group at the 5xe2x80x2 position of the mother nucleoside, such as 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine. Appropriate third functional groups will depend on the nature of the cooperating function on optional linker group L2, if present, and may include amino, hydoxy, carbonyl, sulfonyl, phosphoryl, phosphonyl, carbamoyl and the like. If L2 is absent, this third functional group or, first linker L1 will typically comprise a carboxyl function which can esterify with the 5xe2x80x2-O group of the nucleoside analogue.
Preferably the functional groups on the trifunctional linker which cooperate with R1 and R2 are hydroxyl functions and the linkage is an ester linkage with the carboxyl functions of an R1 fatty acid, if present, and R2. A further preferred embodiment comprises a free hydroxy group as R1 and an hydroxyl function on the linker esterified to the carboxy function of R2. An alternative embodiment comprises an (optionally protected) carboxyl group as R1 and an hydroxyl function on the linker esterified to a carboxy function on R2.
Useful trifunctional L1 group, especially for esterifying directly to the nucleoside include linkers of the formula IIa or IIb; 
where A and Axe2x80x2 define a respective ester linkage between an hydroxy on the linker and the carboxy on R1 or R2 or an ester linkage between a carboxy on the linker and the hydroxy on R1 as a fatty alcohol, or an amide linkage between an amine on the linker and a carboxy on R1 or R2, or amide linkage between a carboxy on the linker and an amine on R1 or R2, or one of A and Axe2x80x2 is as defined and the other is hydroxy, amino or carboxy in the event that R1 itself is a free hydroxy, amino or carboxy group.
Rx is H or C1-C3 alkyl,
T is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
Alk is absent, C1-C4 alkyl or C2-C4 alkenyl, optionally substituted as described above; and
m and n are independently 0, 1 or 2.
In a a preferred embodiment of this aspect of the invention, the R1 or R1 groups are each esterified to a respective one of the leftmost functional hydroxy groups (viz A and Axe2x80x2) of Formula IIa, while the carbonyl moiety to the right is esterified, optionally via a second linker group L2, to the 5xe2x80x2-O-group of the nucleoside.
Alternatively the L1 group may comprise a linker of the formula IIb: 
where
Ar is a saturated or unsaturated, preferably monocyclic carbo- or heterocycle with 5 or 6 ring atoms; and
A, Axe2x80x2, T, Alk, m and n are as defined above.
In Formula IIb, Ar is preferably an aromatic group such as pyridine or especially phenyl, such as aromatic moieties wherein the arms bearing the R1 and R2 groups are respectively para and ortho, meta and ortho, both ortho, or preferably para and meta, both para or both meta to die remainder of the linker.
In formula IIa and IIb, the following combinations of m, n and Alk are presently favoured:
As R1 and R2 may have different structures, it will be apparent that many L1 groups, particularly those of formula IIa, will define chiral structures and the invention includes all enaritiomers thereof, as racemates or as preparations of  greater than 80%, preferably  greater than 95% enantiomerically pure compound.
A favoured structure within formula IIa has the formula: 
which breaks down in vivo to the nature identical glyceric acid. Particularly preferred are compounds derived from D-glyceric acid.
Thus preferred compounds of formula I include:
5xe2x80x2-O-[(S,R) 2,3-bis-(L-valyloxy)-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[(S,R) 2,3-bis-(L-isoleucyloxy)-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
and most preferably
5xe2x80x2-O-[(R) 2,3-bis-(L-valyloxy)-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[(R) 2,3-bis-(L-isoleucyloxy)-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine;
and their pharmaceutically acceptable salts.
A particularly preferred group of trifunctional linkers comprise glycerol derivatives of the formula IIc 
where A is hydrogen, the acyl residue of an aliphatic L-amino acid ester or the acyl residue of a fatty acid ester, Axe2x80x2 is the acyl residue of an aliphatic amino acid residue and D is a C2-C6 saturated or unsaturated dicarboxylic acid residue. Trifunctional linkers of the formula IIc are hydrolysed or otherwise break down in vivo to release the nature identical compounds glycerol the L-amino acid, the fatty acid (if present) and the dicarboxylic acid, each of which are generally safely metabolised and/or excreted by the body. Preferably A and Axe2x80x2 are both residues of an aliphatic amino acid, most preferably the same residue, particularly residues of L-valine or L-isoleucine.
In the event that the dicarboxylic acid moiety in the derivative of formula IIc is esterified directly to the 5xe2x80x2 hydroxy function (or equivalent) on the nucleoside, an alternative analysis would be to define the glycerol moiety as trifunctional linker L1 and the dicarboxylic acid moiety as difunctional linker L2.
Particularly preferred dicarboxylic acid residues include those derived from oxalic, malonic, tartronic, succinic, maleic, fumaric, malic, tartaric, glutaric, glutaconic, citaconic, itaconic, ethidine-malonic, mesaconic, adipic, allylmalonic, propylidenemalonic, hydromuconic, pyrocinchonic and muconic acids and the like. The dicarboxylic acid residue may be optionally substituted, for example with the substituents listed above in respect of R1 as a fatty acid. Hydroxy substituents can in turn be esterified with a further L-amino acid or fatty acid residue.
Several of the abovementioned dicarboxylic acids can themselves define a trifunctional linker. For instance hydroxy-substituted dicarboxylic acids such as tartaric acid or malic acid offer a number of configurations within the scope of the invention. Taking tartaric acid as an example a carboxyl function is available for esterification with the 5xe2x80x2-hydroxyl function of a nucleoside (optionally via difunctional linker L2). The hydroxy functions are available for esterification with the respective carboxyl functions of R2 and an R1 fatty acid or amino acid while the remaining carboxy group can be free, or optionally protected, for instance with a conventional pharmaceutically acceptable ester such as the methyl or ethyl ester. Alternatively the optional protection of the free carboxy function can itself comprise an ester with an R1 fatty alcohol, with one or both hydroxyl functions being esterified to R2: 
Favoured linkers of the tartaric acid series above can be generically depicted as Formula IIe: 
and isomers where R1 and R2 are reversed, where R1 and R2 are as shown above, p, q and r are each independently 0 to 5, preferably 0 and 1 and Ry is the free acid, and R1 ester or a conventional pharmaceutically acceptable carboxy protecting group, such as the methyl, benzyl or especially the ethyl ester.
Favoured linkers of the malic series have the formula IIf: 
where Ry, p, q and R2 are as defined above, preferably those where p and q are zero.
Preferred compounds of this aspect of the invention thus include:
5xe2x80x2-O-[3-methoxycarbonyl-2-valyloxy-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[3-benzyloxycarbonyl-2-valyloxy-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[3-methoxycarbonyl-2-isoleucloxy-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5 xe2x80x2-O-[3-benzyloxycarbonyl-2-isoleucyloxy-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[4-methoxycarbonyl-2,3-bis-valyloxy-butyryl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[4-benzyloxycarbonyl-2,3-bis-valyloxy-butyryl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[4-methoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[4-benzyloxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine;
particularly those derived from L-malic acid and L-tartaric acid; and corresponding derivatives employing conventional pharmaceutically acceptable esters on the terminal carboxy function.
Particularly favoured compounds include:
5xe2x80x2-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine,
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanosine, expecially the isomers derived from L-malic and L-tartaric acid.
In a related alternative aspect of the invention one of R1 and R2 is omitted. Representative compounds of this aspect of the invention include those of the formula Ia: 
where Alk is optionally substituted C1-C4 alkyl or C2-C4 alkenyl and R2 is the ester residue of an aliphatic L-amino acid or a fatty acid as defined for R1 and R2 above. Linkers of this aspect of the invention are conveniently prepared from xcex1-hydroxy xcfx89-carboxylic acids such as carbonic acid, glycollic acid, hydroxypropanoic acid, hydroxybutyric acid, hydroxyvaleric acid or hydroxycaproic acid.
Representative compounds of Formula Ia include:
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[3-(L-valyloxy)-propionyl]guanosine
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5xe2x80x2-O-[5-(L-valyloxy)-pentanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5xe2x80x2-O-[6-(L-valyloxy)-hexanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[3-(L-isoleuclyoxy)-propionyl]guanosine
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5xe2x80x2-O-[5-(L-isoleucyloxy)-pentanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5xe2x80x2-O-[6-(L-isoleucyloxy)-hexanoyl]guanosine,
and pharmaceutically acceptable salts thereof.
Particularly favoured compounds of formula Ia include:
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5xe2x80x2-O-[4-(L-valyloxy)-butyryl]guanosine; and
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5xe2x80x2-O-[4-(L-isoleucyloxy)-butyryl]guanosine and
pharmaceutically acceptable salts thereof. In these compounds hydrolysis and removal of the R2 group in vivo leaves a reactive terminal radical which will tend to cyclize and prompt the effective release of the mother nucleoside.
In a related alternative aspect of the invention, R1 as a fatty acid residue is itself used as the linker, with the aliphatic L-amino acid residue of R2 being esterified/amide bonded to an amino, hydroxy or carboxy function on the fatty acid alkyl chain, for example on the xcex2-carbon. In this embodiment the fatty acid of R1 is esterified directly on the 5xe2x80x2-hydroxy (or equivalent) function of the nucleoside, generally with the R2 group already esterified/amide bonded thereon. Alternatively, the functionalised fatty acid (the carboxy/hydroxy/amino function being appropriately protected) can be first esterified to the nucleoside and deprotected prior to coupling with R2. Linkers in accordance with a preferred embodiment of this aspect have the formula IId: 
where R2 is the residue of an aliphatic L-amino acid and, p is 0, 1 or 2-20 (optionally including a double bond) and q is 0-5, preferably 0. Representative compounds include:
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-butyryl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-hexanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-octanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-decanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-dodecanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-myristoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-palmitoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-stearoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-docosanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-eicosanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-butyryl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-hexanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-octanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-decanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-dodecanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-myristoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-palmitoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-stearoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-docosanoyl]guanosine,
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)-eicosanoyl]guanosine,
and the corresponding n-3 and n-6 monounsaturated analogues, such as 6 or 9 octadecenoyl derivatives.
In formula IId, p and q are preferably 0, thus defining lactic acid derivatives, preferably L-lactic acid derivatives, such as
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-valyloxy)-propionyl]guanosine; and
2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-5-O-[2-(L-isoleucyloxy)propionyl]guanosine and
pharmaceutically acceptable salts thereof, as the breakdown products, lactic acid and the amino acid are both well accepted physiologically.
The expression bifunctional in the context of second linker group L, means that the the linker has two functions enabling it to act a spacer or bridge between the first linker group L) and the 5xe2x80x2-O group of the nucleoside. For instance the optional group L2 may comprise a linker of the formula IIIa: 
where R4 and R4xe2x80x2 are hydrogen or C1-C4 alkyl. In formula IIIa, R4 is preferably hydrogen, methyl ethyl or isopropyl and R4xe2x80x2 is hydrogen Linkers of formula IIIa are convenient as many nucleosides such as the FLG mother compound must first be phosphorylated by cellular enzymes before it can inhibit the viral polymerase. An initial or sequential hydrolysis of compounds of the invention can release a monophosphorylated nucleoside in vivo which is available for immediate conversion to the di- and triphosphate.
Alternatively the optional bifunctional linker group L2 may comprise a structure of the formula IIIb: 
where R4 and R4xe2x80x2 are independently H or C1-C4 alkyl.
A still further group of bifunctional linkers have the formula IIIc: 
As described above, a preferred group of bifunctional linkers comprises xcex1,xcfx89-dicarboxylic C2-C6 alkyl derivatives, such as succinic acid, which are optionally substituted (for instance with the substituents defined above for R1 as a fatty acid) and/or optionally mono or polyunsaturated, such as n-3 or n-6 monounsaturated. Preferred moieties within this class are listed above.
Although the disclosure above has concentrated on glycerol L1 groups in conjunction with dicarboxylic L2 groups, it will be appreciated that a wide variety of trifunctional linkers are appropriate with dicarboxylic L2 groups, for instance structures of the formula IIa and IIb above lacking the rightmost carbonyl.
The invention further includes double prodrugs comprising R1(R2) L1L2-derivatives of conventional FLG prodrugs, which conventional pro drugs release FLG in vivo, such as prodrug derivatives at the 2 and 6 positions of the FLG guanine base. Examples of such conventional FLG-prodrugs include compounds of the formula IV: 
where R1, R2, L1 and L2 are as defined above; and
R3 is H, N3, NH2, or OH or a pharmaceutically acceptable ether or ester thereof; and
R3xe2x80x2 is an aromatic bond or hydrogen;
Potential pharmaceutically acceptable esters for R3 include the fatty acids described in relation to R1 above, such as stearolyl, oleoyl etc or shorter esters such as acetyl or butyryl. Other potential esters include the amino acid derivatives of R2 or esters of phosphoric acid, such as monophosphate. Alternative esters include the corresponding fatty acid or alkylaryl carbonate, carbamate or sulphonic esters.
Suitable pharmaceutically acceptable ethers for R3 include C1-C6 alkyl, cycloallyl, C6-C12 alkaryl such as benzyl or methylpyridyl, any of which may be optionally substituted as for R1 above. Convenient ethers include those described in the abovementioned WO 93 13778 such as n-propoxy, cyclobutoxy, cyclopropanylamino, piperidino or pyrrolidino and the like.
The invention has thus far been described with reference to the monohydroxylated nucleoside FLG, however it will be apparent that corresponding derivatives can be prepared of other monohydroxylated nucleoside analogues, particularly those where the monohydroxy group corresponds to the 5xe2x80x2 hydroxy function of a nucleoside. Thus an additional aspect of the invention provides compounds of the formula Ic: 
where R1, R2, L1 and L2 are as defined above and xe2x80x94O-nuc is the residue of a monohydroxyl bearing D- or L-nucleoside dialogue. Representative nucleosides in accordance with this aspect of the invention include acyclic nucleoside analogues such as acyclovir and cyclic nucleoside analogues such as ddI (didanosine), ddC (zalcitabine), d4T (stavudine). FTCg lamivdine (3TC), 1592U89 (4-[2-amino-6-(cyclopropylamino)-9H-pulin-9-yl]-2-cyclopentene-1-methanol), AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane), F-ddA and the like, each of which are well known in the nucleoside art. A number of monohydric L-nucleosides are under development and the invention will also ad utility on this compounds. Compounds within this aspect of the invention will also find utility in the corresponding indications to the mother compounds, for instance herpesvirus infections for acyclovir derivatives, HIV for ddI, stavudine, ddC, lamivudine, AZT and 1592U89, HBV for lamivudine, FTC etc.
A favoured subgroup within Formula Ic comprises derivatives of monohydric nucleosides of the formula Icxe2x80x2: 
where A, Axe2x80x2, Alk and O-nuc are as defined above. Formula Icxe2x80x2 above depicts compounds wherein A and Axe2x80x2 depend from the 1 and 3 positions of the glycereol moiety and L2 depends from the glycerol 2 position. In alternative isomers A and Axe2x80x2 depend 1 and 2 or 2 and 3 and L2 from 3 or 2 respectively.
Representative compounds within this aspect of the invention include:
4xe2x80x2-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]acyclovir,
4xe2x80x2-O-[3 -((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]acyclovir,
5xe2x80x2-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]lamivadine,
5xe2x80x2-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]lamivudine,
5xe2x80x2-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((1,3-bis-1-valyloxy)-2-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((1-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]DAPD,
5xe2x80x2-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine
5xe2x80x2-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine,
5xe2x80x2-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine,
5xe2x80x2-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine,
5xe2x80x2-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-deoxyinosine,
5xe2x80x2-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine,
5xe2x80x2-O-[3-(1,3-bis-L-isoleucyloxy-2-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine,
5xe2x80x2-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]-2xe2x80x2,3xe2x80x2-dideoxyinosine,
5xe2x80x2-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]stavudine,
5xe2x80x2-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]stavudine,
5xe2x80x2-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]stavudine,
5xe2x80x2-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]stavadine,
5xe2x80x2-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]stavudine,
5xe2x80x2-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]stavudine,
5xe2x80x2-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]stavudine,
5xe2x80x2-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]stavudine,
the corresponding derivatives of -[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, and pharmaceutically acceptable salts thereof.
A preferred group of compound sis based on glyceric acid, including
5xe2x80x2-O-[(S) 2,3-bis-(L-valyloxy)-propionyl]-stavudine
5xe2x80x2-O-[(S) 2,3-bis-(L-isoleucylaxy)-propionyl]-stavudine,
5xe2x80x2-O-[(S) 2,3-bis-(L-valyloxy)-propionyl]-dideoxyiosine
5xe2x80x2-O-[(S) 2,3-bis-(L-isoleucyloxy)-propionyl]-dideoxyinosine
5xe2x80x2-O-[(S) 2,3-bis-(L-valyloxy)-propionyl]-DAPD
5xe2x80x2-O-[(S) 2,3-bis-(L-isoleucyloxy)-propionyl]-DAPD
5xe2x80x2-O-[(S) 2,3-bis-(L-valyloxy)-propionyl]-lamivudine
5xe2x80x2-O-[(S) 2,3-bis-(L-isoleucyloxy)-propionyl]-lamivudine
5xe2x80x2-O-[(S) 2,3-bis-(L-valyloxy)-propionyl]-acyclovir
5xe2x80x2-O-[(S) 2,3-bis-(L-isoleucyloxy)-propionyl]-acyclovir
and pharmaceutically acceptable salts thereof.
An alternative subset of compounds within this aspect of the invention comprise those of the formula Id: 
where Rz and Alk are as defined for formula Ia and O-nuc is as defined above.
Representative compounds of formula Id include
4xe2x80x2-O-[4-(L-valyloxy)-propionyl]acyclovir,
4xe2x80x2-O-[5-(L-valyloxy)-pentanoyl]acyclovir,
4xe2x80x2-O-[6-(L-valyloxy)-hexanoyl]acyclovir,
4xe2x80x2-O-[4-(L-isoleucyloxy)-propionyl]acyclovir,
4xe2x80x2-O-[5-(L-isoleucyloxy)-pentanoyl]acyclovir,
4xe2x80x2-O-[6-(L-isoleucyloxy)hexanoyl]acyclovir,
5xe2x80x2-O-[4-(L-valyloxy)-propionyl]ddI,
3xe2x80x2-O-[5-(L-valyloxy)-pentanoyl]ddI,
5xe2x80x2-O-[6-(L-valyloxy)-hexanoyl]ddI,
5xe2x80x2-O-[4-(L-isoleucyloxy)-propionyl]ddI,
5xe2x80x2-O-[5-(L-isoleucyloxy)-pentanoyl]ddI,
5xe2x80x2-O-[6-(L-isoleucyloxy)-hexanoyl]ddI,
5xe2x80x2-O-[4(L-valyloxy)-propionyl]stavudine,
5xe2x80x2-O-[5-(L-valyloxy)-pentanoyl]stavudine,
5xe2x80x2-O-[6-(L-valyloxy)-hexanoyl]stavudine,
5xe2x80x2-O-[4-(L-isoleucyloxy)-propionyl]stavudine,
5xe2x80x2-O-[5-(L-isoleucyloxy)-pentanoyl]stavudine,
5xe2x80x2-O-[6-(L-isoleucyloxy)-hexanoyl]stavudine,
5xe2x80x2-O-[4-(L-valyloxy)-propionyl]DAPD,
5xe2x80x2-O-[5-(L-valyloxy)-pentanoyl]DAPD,
5xe2x80x2-O-[6-(L-valyloxy)-hexanoyl]DAPD,
5xe2x80x2-O-[4-(L-isoleucyloxy)-propionyl]DAPD,
5xe2x80x2-O-[5-(L-isoleucyloxy)-petanoyl]DAPD,
5xe2x80x2-O-[6-(L-isoleucyloxy)-hexanoyl]DAPD,
5xe2x80x2-O-[4-(L-valyloxy)-propionyl]lamivudine,
5xe2x80x2-O-[5-(L-valyloxy)-pentanoyl]lamivudine,
5xe2x80x2-O-[6-(L-valyloxy)-hexanoyl]lamivudine,
5xe2x80x2-O-[4-(-isoleucyloxy)-propionyl]lamivudine,
5xe2x80x2-O-[5-(L-isoleucyloxy)-pentanoyl]lamivudine,
5xe2x80x2-O-[6-(L-isoleucyloxy)-hexanoyl]lamivudine,
and the corresponding derivatives of 4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol.
Particularly preferred compounds within Formula Id include:
4xe2x80x2-O-[4-(L-valyloxy)-butyryl]acyclovir,
4xe2x80x2-O-[3-(L-isoleucyloxy)-butyryl]acyclovir,
5xe2x80x2-O-[4-(L-valyloxy)-butyryl]ddI,
5xe2x80x2-O-[3-(L-isoleucyloxy)-butyryl]ddI,
5xe2x80x2-O-[4-(L-valyloxy)-butyryl]stavadine,
5xe2x80x2-O-[3-(L-isoleucyloxy)-butyryl]stavudine,
5xe2x80x2-O-[4-(L-valyloxy)-butyryl]DAPD,
5xe2x80x2-O-[3-(L-isoleucyloxy)-butyryl]DAPD,
5xe2x80x2-O-[4-(L-valyloxy)-butyryl]lamivudine,
5xe2x80x2-O-[3-(L-isoleucyloxy)-butyryl]lamivudine,
and the corresponding derivatives of 4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol; and pharmaceutically acceptable salts thereof. In these compounds hydrolysis and removal of the R2 group in vivo leaves a reactive terminal radical which will tend to cyclize and prompt the effective release of the mother nucleoside.
Similarly the invention extends to compounds of the formula If: 
where R1, R2, Ry, p, q, r and o-nuc are as defined above.
Favoured compounds of this aspect of the invention include:
5xe2x80x2-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-ddI,
5xe2x80x2-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-ddI
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-ddI,
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-ddI,
4xe2x80x2-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-acyclovir,
4xe2x80x2-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-acyclovir,
4xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-acyclovir,
4xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-acyclovir,
5xe2x80x2-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-DAPD,
5xe2x80x2-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-DAPD
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-DAPD,
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-DAPD,
5xe2x80x2-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-stavudine,
5xe2x80x2-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-stavudine
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-stavudine,
5xe2x80x2-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-lamivudine,
5xe2x80x2-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-lamivudine
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-lamivudine,
5xe2x80x2-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-lamivudine,
and the corresponding malic and tartric derivatives of 4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and pharpamceutically acceptable salts thereof; in each case the isomers derived from L-tartrate and L-malate derivatives being preferred.
The invention also extends to compounds of the formula Ig 
where R2,p, q and O-nuc are as defined above.
Preferred compounds of formula Ig include:
4xe2x80x2O-[2-(L-valyloxy)-propionyl]acyclovir,
4xe2x80x2O-[2-(L-isoleucyloxy)-propionyl]acyclovir
5xe2x80x2O-[2-(L-valyloxy)-propionyl]ddI,
5xe2x80x2O-[2-(L-isoleucyloxy)-propionyl]ddI,
5xe2x80x2O [2-(L-valyloxy)-propionyl]stavudine,
5xe2x80x2O-[2-(L-isoleucyloxy)-propionyl]stavudine
5xe2x80x2O-[2-(L-valyloxy)-propionyl]lamivudine,
5xe2x80x2O-[2-(L-isoleucyloxy)-propionyl]lamivudine,
5xe2x80x2O-[2-(L-valyloxy)-propionyl]DAPD,
5xe2x80x2O-[2-(L-isoleucyloxy)-propionyl]DAPD
and the corresponding derivatives of 4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol;and pharmaceutically acceptable salts thereof. The breakdown products of such compounds, lactic acid and the amino acid, are both well accepted physiologically.
The compounds of the invention can form salts which form an additional aspect of the invention. Appropriate pharmaceutically acceptable salts of the compounds of Formula I include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. The compounds of Formula I may in some cases be isolated as the hydrate.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (John Wiley and Sons, New York, 1981), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Favoured N-protecting groups include formyl, acetyl, allyl, F-moc, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).
Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsilyl, triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like, substituted ethyl ethers such as 1-ethoxymethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such as trityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especially the chloride). Ester hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like.
In keeping with the usual practice with retroviral and HBV inhibitors it is advantageous to co-administer one to three or more additional antivirals, such as AZT, ddI, ddC, d4T, 3TC, H2G, foscarnet, ritonavir, indinavir, saquinavir, nevirapine, delaviridine, Vertex VX 478 or Agouron AG1343 and the like in the case of HIV or lamivudine, interferon, farnciclovir etc in the case of HBV. Such additional antivirals will normally be administered at dosages relative to each other which broadly reflect their respective therapeutic values, Molar ratios of 100:1 to 1:100, especially 25:1 to 1:25, relative to the compound or salt of formula I will often be convenient. Administration of additional antivirals is generally less common with those antiviral nucleosides intended for treating herpes infections.
While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers/excipients and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of Formula I or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of pharmaceutical formulations involves intimate mining of pharmaceutical excipients and the active ingredient in salt form, then it is often preferred to use excipients which are non-basic in nature, i.e. either acidic or neutral.
Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
With regard to compositions for oral administration (e.g. tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch, fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
A still further aspect of the invention provides a method for the preparation of a compound of Formula I or Ic comprising the acylation of the nucleoside, represented here by FLG, Formula V, typically at the 5xe2x80x2 hydroxy group: 
in which R1(R2)L1X represents an activated acid, such as the carboxylic derivatives of Formula IIa or IIb, where R1, R2, and L1 are as defined above or protected derivatives thereof. Alternatively the activated acid may comprise a compound of the formula R1(R2)glycerol-D-X, where R1, R2 and D are as defined in formula IIc or an activated Rzxe2x80x94O-Alk-C(xe2x95x90O)X derivative in the case of compounds of formula Ia. In the later cases the linkers may be built up sequentially by first esterifying a suitably protected D or xcfx89-hydroxy carboxylic acid to the nucleoside, deprotecting the terminal carboxy or hydroxy function and esterifying the suitably protected glycerol or Rz moiety thereon.
The activated derivative used in the acylation may comprise e.g, the acid halide acid anhydride, activated acid ester or the acid in the presence of coupling reagent, for example dicyclohexylcarbodiimide. Representative activated acid derivatives include the acid chloride, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinamide derived esters, N-hydroxyphtalimide derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like. Further activated acids include those where X in the formula RX represents an ORxe2x80x2 moiety where R is R2 as defined herein, and Rxe2x80x2 is, for example COCH3, COCH2CH3 or COCF3 or where X is benzotriazole.
Corresponding methodology will be applicable when the invention is applied to other monohydroxylated nucleosides, that is the activated derivative is correspondingly esterified to the free 5xe2x80x2 hydroxy (or equivalent) of monohydric nucleosides such as acyclovir, ddI, FTC, lamivudine, 1592U89,DAPD, P-ddA and the like.
The intermediates used in the above methods themselves define novel compounds, especially those of the formula: IIcxe2x80x2
where A, Axe2x80x2 and Alk are as defined above (A and Axe2x80x2 being optionally protected with conventional protecting groups) and X represents the free acid or an activated acid as illustrated above.
Corresponding compounds to those of formula IIcxe2x80x2 include:
malonic acid 2,3-bis-(L-valyloxy)-propyl ester,
malonic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,
malonic acid 2,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,
malonic acid 2,3-bis-(L-Boc-L-valyloxy)-propyl ester,
malonic acid 2,3-bis-(L-isoleucyloxy)-propyl ester,
malonic acid 2,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,
malonic acid 2,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,
malonic acid 2,3-bis-(L-Boc-L-isoleucyloxy)-propyl ester,
succinic acid 2,3-bis-(L-valyloxy)-propyl ester,
succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,
succinic acid 2,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,
succinic acid 2,3-bis-(N-Boc-L-valyloxy)-propyl ester,
succinic acid 2,3-bis-(L-isoleucyloxy)-propyl ester,
succinic acid 2,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,
succinic acid 2,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,
succinic acid 2,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,
glutaric acid 2,3-bis-(L-valyloxy)-propyl ester,
glutaric acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,
glutaric acid 2,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,
glutaric acid 2,3-bis-(N-Boc-L-valyloxy)-propyl ester,
glutaric acid 2,3-bis-(L-isoleucyloxy)-propyl ester,
glutaric acid 2,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,
glutaric acid 2,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,
glutaric acid 2,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,
and the corresponding acid halides, in particular the chloride, acid anhydrides and diesters of each of the above, for instance
succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,4-methoxybenzyl ester
succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester, 1,1-dimethylethyl ester, etc.
A preferred group of compounds in Formula IIcxe2x80x2 include
malonic acid 1,3-bis-(L-valyloxy)-propyl ester,
malonic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,
malonic acid 1,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,
malonic acid 1,3-bis-(N-Boc-L-valyloxy)-propyl ester,
malonic acid 1,3-bis-(L-isoleucyloxy)-propyl ester,
malonic acid 1,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,
malonic acid 1,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,
malonic acid 1,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,
succinic acid 1,3-bis-(L-valyloxy)-propyl ester,
succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,
succinic acid 1,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,
succinic acid 1,3-bis-(N-Boc-L-valyloxy)-propyl ester,
succinic acid 1,3-bis-(L-isoleucyloxy)-propyl ester,
succinic acid 1,3-bis-(N-CZ-L-isoleucyloxy)-propyl ester,
succinic acid 1,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,
succinic acid 1,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,
glutaric acid 1,3-bis-(L-valyloxy)-propyl ester,
glutaric acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,
glutaric acid 1,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,
glutaric acid 1,3-bis-(N-Boc-L-valyloxy)-propyl ester,
glutaric acid 1,3-bis-(L-isoleucyloxy)-propyl ester,
glutaric acid 1,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,
glutaric acid 1,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,
glutaric acid 1,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,
and the corresponding acid halides, in particular the chloride, acid anhydrides and diesters of each of the above, for instance
succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,4-methoxybenzyl ester
succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester, 1,1dimethylethyl ester, etc.
A further preferred group of intermediates comprises those of the formula IIaxe2x80x2; 
where Rx, Alk, m, n and T are as described above, A and Axe2x80x2 represent acyl residues of Lxe2x80x2-aliphatic amino acids (N-protected as necessary) esterified to hydroxy functions on the linker or one of A and Axe2x80x2 is the acyl residue and the other is a free hydroxy group, and X represents the free acid or an activated acid as illustrated above. Preferably A and Axe2x80x2 are the same amino acid residue.
Other novel intermediates include the free or activated acid precursors of compounds of the formula Ia such as:
3-N-Boc-L-valyloxypropanoic acid, 3-N-Fmoc-L-valyloxypropanoic acid, 3-N-CBZ-L-valyloxypropanoic acid, 3-N-Boc-L-isoleucyloxypropanoic acid, 3-N-Fmoc-L-isoleucyloxypropanoic acid, 3-N-CBZ-L-isoleucyloxypropanoic acid, 4-N-Boc-L-valyloxybutyric acid, 4-N-Fmoc-L-valyloxybutyric acid, 4-N-CBZ-L-valyloxybutyric acid, 4-N-Boc-L-isoleucyloxybutyric acid, 4-N-Fmoc-L-isoleucyloxybutyric acid, 4-N-CBZ-L-isoleucyloxybutyric acid and the like;
and the activated derivatives, such as the acid halides
Further novel intermediates include precursors of compounds of the formula IIe and IIf above, especially those derived from xe2x80x9cnaturalxe2x80x9d configurations such a L-malic and L-tartaric acid; for instance:
3-ethoxycarbonyl-2-valyloxy-propionic acid
3-ethoxycarbonyl-2-isoleucyloxy-propionic acid
4-ethoxycarbonyl-2,3-bis-valyloxy-butyric acid
4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyric acid
3-t-butoxycarbonyl-2-valyloxy-propionic acid
3-t-butoxycarbonyl-2-isoleucyloxy-propionic acid
4-t-butoxycarbonyl-2,3-bis-valyloxy-butyric acid
4-t-butoxycarbonyl-2,3-bis-isoleucyloxy-butyric acid
3-benzyloxycarbonyl-2-valyloxy-propionic acid
3-benzyloxycarbonyl-2-isoleucyloxy-propionic acid
4-benzyloxycarbonyl-2,3-bis-valyloxy-butyric acid
4-benzyloxycarbonyl-2,3-bis-isoleucyloxy-butyric acid, and the like;
the corresponding compounds wherein the amino acid is N-protected, particularly with a protecting group allowing selective deprotection of the N-protective group without removal of the carboxy protecting group; and the corresponding, activated derivatives such as the acid halides.
Still further novel intermediates include precursors corresponding to structure IId, such as;
2-(L-valyloxy)propanoic acid, 2-(N-Boc-L-valyloxy)propanoic acid, 2-(N-Fmoc-L-valyloxy)propanoic acid, 2-(N-CBZ-L-valyloxy)propanoic acid, 2-(L-isoleucyloxy)propanoic acid, 2-(N-Boc-L-isoleucyloxy)propanoic acid, N-(Fmoc-L-isoleucyloxy)propanoic acid, N-(CBZ-L-isoleucyloxy)propanoic acid,
2-(L-valyloxy)butyric acid, 2-(N-Boc-L-valyloxy)butyric acid, 2-(N-Fmoc-L-valyloxy)butyric acid, 2-(N-CBZ-L-valyloxy)butyric acid, 2-(L-isoleucyloxy)butyric acid, 2-(N-Boc-L-isoleucyloxy)butyric acid, N-(Fmoc-L-isoleucyloxy)butyric acid, N-(CBZ-L-isoleucyloxy)butyric acid, and the like; and activated derivatives thereof, such as the acid halides.
Preparation of 3xe2x80x2 fluoronucleosides such as those of formula V has been extensively reviewed by Herdiwijn et al. in Nucleosides and Nucleotides 8(1) 65-96(1989), which is hereby incorporated by reference. The preparation of other monohydric nucleosides such as acyclovir, ddI (didanosie), ddC (zalcitabine), d4T (stavudine), FTC, lamivudine (3TC), 1592U89(4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol), AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane), F-ddA and the like are well known and extensively described in the literature.
The reactive derivatives of the R1(R2)L1L2X group may be pre-formed or generated in situ by the use of reagents such as dicyclohexylcarbodiimide (DCC) or O-(1H-benzotriazol-1-yl) N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TBTU). When an acid halide, such as the acid chloride is used, a tertiary amine catalyst, such as triethylamine, N,Nxe2x80x2-dimethylaniline, pyridine or dimethylaminopyridine may be added to the reaction mixture to bind the liberated hydrohalic acid.
The reactions are preferably carried out in an unreactive solvent such as N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or a halogenated hydrocarbon, such as dichloromethane. If desired, any of the above mentioned tertiary amine catalysts may be used as solvent, taking care that a suitable excess is present. The reaction temperature can typically be varied between 0xc2x0 C. and 60xc2x0 C., but will preferably be kept between 5xc2x0 and 50xc2x0 C. After a period of 1 to 60 hours the reaction will usually be essentially complete. The progress of the reaction can be followed using thin layer chromatography (TLC) and appropriate solvent systems. In general, when the reaction is completed as determined by TLC, the product is extracted with an organic solvent and purified by chromatography and/or recrystallisation from an appropriate solvent system.
By-products where acylation has taken place on the nucleoside base can be separated by chromatography, but such misacylation can be minimized by controlled reaction conditions. These controlled conditions can be achieved, for example, by manipulating the reagent concentrations or rate of addition, especially of the acylating agent, by lowering the temperature or by the choice of solvent. The reaction can be followed by TLC to monitor the controlled conditions. It may be convenient to protect the 6-oxo group on the base and especially the 2 amino with conventional protecting groups to forestall misacylation.
Compounds of Formula IV in which R3 is hydrogen may be prepared by 6-activating the corresponding guanine compound of Formula I (wherein the exposed amino function of the amino acid residue of R2 is optionally protected with conventional N-protecting groups) with an activating group such as halo. The thus activated 6-purine is subsequently reduced to purine, for instance with a palladium or nickel catalyst and deprotected to the desired compound of Formula IV or Formula V.
Compounds wherein R3 is an R1 or other ester may be prepared by conventional esterification (analogous to the esterification described above) of the corresponding hydroxy compound of Formula I or Formula V, optionally after conventional N-protecting the exposed amine function of the amino acid residue of R2 and/or R3. Compounds wherein R3 is an ether may be prepared analogously to the process disclosed in the abovementioned WO 93 13778, again in conjunction with optional N-protection of exposed amine groups. Compounds wherein R3 is an azide can be prepared as described in WO 97 09052.
Intermediates of the formula IId are conveniently prepared by acylation of a carboxy-protected hydroxy alkanoic acid, typically a 2-hydroxy-1-alkanoic acid, with the appropriate activated and N-protected R2 derivative, such as N-CBZ valyl or isoleucyl in conjunction with a conventional coupling reagent such as DMAP/DCC or with the amino acid halide. The carboxy protecting group is then removed, for instance by acid hydrolysis and the resulting intermediate is activated as described above or the free acid is used in conjunction with a coupling reagent to esterify the the nucleoside under conventional esterfication conditions.
Compounds within the scope of the invention are also conveniently prepared by the methodology in the immediately preceding paragraph, namely esterification of a carboxy protected xcex1-hydroxy, xcfx89-carboxy acid, such as glycollic acid, lactic acid, hydroxybutyric acid etc with the appropriate N-protected R2 derivative, either as the free acid in conjunction with a coupling agent or activated, for instance to the corresponding acid halide. The carboxy protecting group is removed and the resulting intermediate esterified with the nucleoside with the methodology described above.
Compounds comprising a structure of the formula IIe or IIf are prepared by carboxy protecting the terminal carboxy groups of the respective dicarboxylic acid, such as L-tartaric acid or L-malic acid, with conventional carboxy protecting groups such as benzyl. The free hydroxy group(s) are then esterified with conventional esterification techniques, such as DMAP and DCC in DMF with the appropriate N-protected R2 amino acid, such as N-Boc-L-valyl or N-Boc-L-isoleucyl. The benzyl carboxy protecting groups are removed and the resulting product is esterified to the 5xe2x80x2-hydroxy function of a monohydric nucleoside, using conventional conditions, such as those in the accompanying Examples. Finally, the free carboxy function is esterified with an R1 group or, more preferably a conventional pharmaceutically acceptable ester, such as the ethyl ester.
Compounds comprising a phosphorylated moiety III may be prepared by reacting 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoroguanine-5-monophosphate with a compound of Formula VIa 
where Ha is halo, such as chloro, iodo or bromo, in analagous conditions to those described in U.S. Pat. Nos. 4,337,201, 5,227,506,WO 94/13682and WO 94/13324,Starret et al J Med Chem 37 1857-1864(1994) and Iyer et al Tetrahedron Lett 30 7141-7144(1989) which are incorporated herein by reference. The monophosphate can be prepared by conventional phosphorylation of FLG, as described, for instance, in Herdwyn et al ibid. Corresponding methodology will apply to the monophosphates of other monohydric nucleosides.
Compounds comprising an optional linker L2 may also be prepared by a two stage process. In particular a compound of the formula ClC(xe2x95x90O)OC(R4)(R4xe2x80x2)Cl can be reacted with the 5xe2x80x2-hydroxy of FLG (optionally protected on the base with conventional protecting groups) as is known in the cephalosporin art. The resulting FLG-5xe2x80x2-Oxe2x80x94C(xe2x95x90O)OC(R4)(R4xe2x80x2)chloride is then reacted with an R1 and R2 bearing trifunctional linker wherein the third function comprises a carboxyl function, such as the potassium salt.
It will be appreciated that trifunctional L1 groups of formula IIa wherein and n and m are 1 and Alk is absent can be prepared from glycerol by regioselective esterification as depicted below in scheme 1by reference to a stearoyl/L-valyl combination. In short R1 and R2 are regioselectively esterified to positions 1 and 3 of the glycerol and position 2 is then converted to the appropriate xe2x80x94Txe2x80x94C(xe2x95x90O)-group, which is then esterified to the 5xe2x80x2-position of the fluoronucleoside or to a cooperating function on L2 (not depicted). Alternatively the hydroxy at position 2 of the glycerol derivative can be esterified with an L2 group containing a cooperating carbonyl function on its left hand end.
L1 groups of formula IIa wherein m is 1, n is 0and Alk is methylene can also be prepared from glycerol by regioselectively esterifying R1 and R2 to positions 1 and 2of the glycerol, as also depicted below in scheme 1, followed by conversion of the hydroxy at position 3 to the appropriate xe2x80x94Txe2x80x94C(xe2x95x90O)-group. The leftmost series of reactions on Scheme 1 shows the situation where R1is esterified to position 1 of the glycerol and R2 is esterified to position 2. The corresponding arrangement where R1 is esterified to position 2 and R2 to position 1 can be achieved by first treating the glycerol with CBz-L-valine/DCC/DMAP/DMF and then protecting the 3 position with pixyl chloride prior to esterifying the fatty acid of R1 to position 2 of the glycerol, deprotecting and converting the 3 position as necessary. 
Although Scheme 1 has been illustrated by reference to a combination wherein R1 is stearoyl and R2 is L-valyl, it will be appreciated that this basic scheme will also be applicable to other amino acids, where present other fatty acids, or using conventional protection groups, to combinations of R2as an amino acid derivative and R1 as hydroxy. Linkers where T comprises an xe2x80x94NH-group can be prepared by analogous regioselective esterification followed by conversion of the free hydroxyl to amine, reduction to azide and reaction with phosgene to form the corresponding chlorocarbamate.
A variation of scheme I allowing the preparation of linkers of the formula IIc. In this variation, the phosgene step shown above is replaced by reaction with an activated dicarboxylic acid, such as succinic anhydride. This results in a glycerol triester (comprising the (optionally protected) R1 ester, the protected R2 ester and the ester of the dicarboxylic acid) and the free carboxy on the dicarboxylic acid is then activated and esterified to the nucleoside in a conventional fashion. Alternatively linkers of formula IIc can be built up in situ on the nucleoside. In this variant, the dicarboxylic acid is esterified to a suitably protected glycerol derivative. This succinyl monoester is then esterified to the 5xe2x80x2-hydroxy function of the nucleoside in a conventional manner. Finally one or both of the protecting groups on the glycerol moiety is replaced with the L-amino acid ester, and ifs present, the remaining protecting group is replaced with a fatty acid ester or removed to leave a free hydroxy group. This is depicted in Scheme IA which illustrates an, example wherein the nucleoside in acyclovir (FLG shown in shadow), the dicarboxylic acid is succinyl and R1 and R2 are both CBZ-protected valyl, but will, of course be applicable to other variations of Formula Ic. In each case coupling conditions means standard esterification conditions such as coupling reagents DMAP, DCC etc or alternatively conversion of the relevant carboxy function to an activated derivative such as the acid chloride or the activated succinic moiety can also comprise the anhydride. 
In a variation of Scheme IA, the succinic anhydride is reacted directly with the nucleoside, thus avoiding the first protection and deprotection steps. A further alternative is to regioselectively esterify the glycerol moiety with the N-protected amino acid moiety(ies), generally in conjunction with protection of the hydroxy function intended for coupling to the nucleoside, followed by deprotection of that hydroxy and coupling to the nucleoside. 
Linkers where m and n are 1, Alk is alkylene or alkenylene and T is a bond can be prepared as shown in Scheme II above. Other permutations of m, n, Alk and the various functions in the trifunctional linker group L1 of formula IIa can be prepared analagously to the above with the corresponding starter materials, such as 1,2,4-trihydroxybutane (CA registry number 3968-00-6), 3,4-dihydroxybutanoic acid (1518-61-2 and 22329-74-4), (S)-3,4-dihydroxybutanoic acid (51267-44-8), (R)-3,4-dihydroxybutanoic acid (158800-76-1), 1,2,5-pentanetriol (51064-73-4 and 14697-46-2), (S)-1,2,5-pentanetriol (13942-73-9), (R)-1,2,5-pentanetriol (171335-70-9), 4,5dihydroxypentanoic acid (66679-29-6 and 129725-14-0), 1,3,5-pentanetriol (4328-94-3) and 3-(2-hydroxyethyl)-1,5-pentanediol (53378-75-9). The preparation of each of these starting materals is described in the references to the respective registry number. Ohsawa et al in Chem Pharm Bull 41 (11) 1906-1909(1993) and Terao et al Chem. Pharm. Bull. 39(3) 823-825(1991) describe the control of the sterochemistry of trifunctional linker groups with lipase P.
The amino acid derivative of R2 and, if present, R1 can alternatively be esterified to the linker group with the 2-oxa-4-aza-cycloalkane-1,3-dione methodology described in international patent application no. WO 94/29311, the contents of which are hereby incorporated by reference.
Linking of the carboxy function of R1 and/or R2 to an amine group on the linker derivative proceeds by conventional peptide chemistry, generally in conjunction with protection of the xcex1-amine with conventional N-protecting groups. Formation of an amide bond between a carboxyl function on the linker and the xcex1-amine group of R2 also proceeds by conventional peptide chemistry, generally in conjunction with protection of the xcex1-carboxy function. Esterification of R1as a fatty alcohol to a carboxy function on the linker proceeds analogously, but conversely, to the above esterification of R1 as a fatty acid.
The above description has centred around monohydric nucleosides derivatised with a linker group which in turn is derivatised with an ester residue of an aliphatic amino acid, and, optionally, the acyl residue of a fatty acid. In a further aspect of the invention, however, said linker group and derivatised aliphatic amino acid ester, but this time without the optional fatty ester, can be applied to a broader range of drags. Thus the invention further provides compounds of the formula Dxe2x80x94Lxe2x80x94R2 where R2 is the amide or ester residue of an aliphatic amino acid, D is a drug residue bearing an accesible function such as an amine, hydroxy, carboxy, phosphonate, phosphinate or phosphoryl function and L is an at least bifunctional linker comprising a first function bound to said accessible function spaced from a second function forming an amide or acyl bond with the aliphatic amino acid.
The prodrugs of this aspect of the invention are distinct from those described in WO98/21233 in that the latter comprise an obligatory fatty acid ester.
Drug residue as used in its conventional significance, that is implying that during linkage a hydrogen or hydroxy has been eliminated from an accessible amino, phosphoryl, phosphinyl, phosphonyl, carboxy or hydroxy function on the Drug; The amine function on the Drug can be a primary amine (xe2x80x94NH2) or a secondary amine (xe2x80x94NHxe2x80x94). The amino acid of R2 may be optionally N-protected in those configurations where it possesses a free amine function.
The expression difunctional in the context of the linker group L means that the linker has at least one hydroxy or amine function available for esterification or amide bonding with R2, or a carboxyl function available for amide bonding with the free xcex1-amine function of R2 . Spaced therefrom on the difunctional linker is a further functional group for linkage to a cooperating function on the Drug such as hydroxy, carboxy, phosphonyl, phosphoryl, phosphinyl and the like.
The linker may in fact be trifunctional, that is the linker has at least three functions including two independently selected from hydroxy, amine or carboxy, the amine and hydroxy function(s) being available for esterification/amide bonding with the carboxyl functions of a pair of R2, or the carboxy function(s) on the linker being available for amide bonding with the free xcex1-amine function of R2. These hydroxy/amine/carboxy functions are spaced from a further functional group for linkage with a cooperating function on the drug, such as hydroxy, carboxy, phosphonyl, phosphoryl, phosphinyl amine etc. Other trifunctional linker groups may comprise a first hydroxy, amine or carboxy function cooperating with R2, a function cooperating with the drug and a further functional group either underivatised such as hydroxy, carboxy, amine etc or alternatively protected with conventional pharmaceutically acceptable protecting groups.
The invention further provides pharmaceutical compositions comprising the compounds of the present broader aspect of the invention and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods of medical treatment or prophylaxis comprising the administration of a compound of the invention to a human or animal suffering from or prone to the ailment to which the respective Drug is applicable.
By the use of the invention the pharmacokinetics of a broad range of orally administered drugs are enhanced, for instance by improving absolute bioavailability or by providing a more even release of the mother compound or by providing for a reduced interpersonal spread in pharmacokinetic performance. However the compounds of the invention are not limited to those based on orally administered drugs as the prodrugs of the invention, when parenterally administered, provide enhanced pharmacokinetic performance, for instance by improving solubility, while still allowing for efficient release of the mother compound.
Linker as used in this second aspect of the invention specifically embraces each and every linker described above in relation to the monohydric nucleoside aspect of the invention (to the extent that these omit a fatty acid ester), including the structures  greater than L1L2 and structures of the formulae IIa, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, (optionally protected) tartaric and malic acid linkers, and linkers depicted in formulae I, Ia, Ic, Icxe2x80x2, Id, If and Ig. However it will be apparent that these linker structures are of wider applicability than the monohydric nucleosides there described.
Convenient linker groups, for instance when the Drug comprises an amine or hydroxy function, include those of the Formulae IIaa or IIxe2x80x2aa 
where A and A"" are independently an ester linkage between an hydroxy on the linker and the carboxy on R2 (or a pair of R2), or an amide linkage between an amine on the linker and a carboxy on R2 or a pair of R2;
Q is a structure: 
or Q is a monocyclic, saturated or unsaturated carbo- or heterocycle with 4, 5 or 6 ring atoms;
Alk is absent, C1-C4 alkylene or C2-C4 alkenylene;
T is a bond,xe2x80x94Oxe2x80x94 or xe2x80x94NR4)xe2x80x94,
V is a bond or a structure of the formula IIbb or IIcc: 
R4 and R4xe2x80x2 are independently hydrogen or C1-C3 alkyl; and
m and n are independently 0, 1 or 2;
In Formulae IIa-IIe, Q as a ring is preferably an aromatic group such as pyridine, furyl, imidazol etc or especially phenyl, such as aromatic moieties wherein the arm(s) bearing the or each R2 group are respectively para and meta or both meta to the remainder of the linker.
Particularly convenient structures when the drug comprises an hydroxy function include the corresponding structures to: formulae IIc*, that is 
formula IIe*, that is 
formula IIf*, that is 
Formula Id*, that is 
Where the Drug comprises a carboxyl function, the linker may comprise a structure of the formulae VIII or VIIIxe2x80x2:
where A, Axe2x80x2, Q, Alk, m, n, are as defined for Formula IIaa and IIxe2x80x2aa. 
Preferably, however, when the Drug comprises a carboxy function, the di- or trifunctional linker group L is a structure of Formulae IIdd or II""dd (that is a compound of Formulae IIaa or II""aa, wherein T is O and V is a structure of the formula IIbb): 
In structure IIdd, R4xe2x80x2 is preferably hydrogen and R4 is ethyl, phenyl, and especially methyl or hydrogen or R4 and R4xe2x80x2 together define isopropyl.
Where the Drug comprises a phosphoryl, phosphinyl or phosphonyl function, the di- or trifunctional linker group L may comprise a structure of the formula IIaa or IIxe2x80x2aa, especially those of the formula IIee or IIxe2x80x2ee: 
where T is a bond,xe2x80x94NHxe2x80x94 orxe2x80x94Oxe2x80x94 and Q and A are as defined above including the cyclic Q structures such as cycloalkyl, phenyl and heterocycles such as furyl, pyridyl etc. In structures IIee and IIxe2x80x2ee, R4xe2x80x2 preferably hydrogen and R4 is methyl, ethyl phenyl and especially hydrogen or R4 and R4xe2x80x2 define isopropyl.
Preferably, however, where the Drug comprises a phosphonyl, phosphinyl or phosphoryl function, the difunctional linker comprises a structure of the formula IIxe2x80x3b: 
where t is a bond,xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94, R41 R4r and R41xe2x80x2 are independently H or C1-C3 alkyl and A is as defined above (or wherein A is a further difunctional linker to which one or more R2 depends as described above). Examples of structures belonging to thee latter possibility for A include those of Formula Va and Vb: 
where, T, q, R2, R41 R41R4r and R4rxe2x80x2 are as defined above. Although formulae Va and Vb depict the dicarboxylate moiety as unbranched, it will be apparent that a wide variety of dicarboxylates will be suitable here, including branched and/or unsaturated and/or substituted dicarboxylic acid derivatives or various lengths, as described in more detail above.
Amongst the preferred configurations for formulae IIxe2x80x2b, Va and Vb, are those wherein T is absent.
Convenient values for the rightmost R4 and R4xe2x80x2 are hydrogen and for the left most R4 and R4, both methyl. Other preferred embodiments comprise structures of the formulae IIxe2x80x2b, Va or Vb wherein the rightmost R4is H and the rightmost R4 is isopropyl, cycloC1-6-alkyl, phenyl or benzyl.
Convenient values of the rightmost q and leftmost q are as follows:
zero: 1
zero:2,
zero:3
1:1
1:zero
2:2
3:zero
3:1.
Still further preferred embodiments comprise structures of the formula IIxe2x80x2b , Va or Vb wherein T isxe2x80x94NHxe2x80x94or xe2x80x94Oxe2x80x94.
In drugs comprising multiple phosphoryl/phosphonate/phosphinate functions, it is generally advantageous that an hydroxy group on each phosphorous moiety is esterified with a structure of Formula IIxe2x80x2e or IIxe2x80x3b etc. Regioselective protecting groups which bridge the phosphate groups of bis phosphonates and thus assist mono and diacylation include Si compounds such as dichlorotetraisopropyldisosiloxane.
Methodology for the derivatisation of phosphorous containing compounds with acyloxyalkyl groups and which can be used analogously for the coupling of the difunctional and trifunctional linkers of the invention is described in U.S. Pat. No. 5,227, 506, WO 94/13682, WO 94/13324, WO 98/04569 Starret et al J Med Chem 37 1857-1864 (1994) and Iyer et al Tetrahedron Lett 30 7141-7144 (1989).
A further aspect of the invention comprises novel intermediates useful in applying structures of the formulae IIxe2x80x3b to a drug and having the formula N-1: 
where A, q, R4, R4xe2x80x2 and T are as defined for formula II""b.
A particularly preferred group of compounds substantially within formula N-1 are those of the formula N-2 
where
R2 is the acyl residue of an aliphatic amino acid,
R3L and R3Lxe2x80x2 are independent H, C1-3alkyl, C3-6cycloalkyl, C1-3alkyl-C1C5cycloalkyl phenyl or benzyl,
R3R and R3Rxe2x80x2 are independent H or C1-3 alkyl
qI is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR3xe2x80x94 or xe2x80x94Oxe2x80x94
R3 is H or C1-3alkyl,;
xe2x80x9cringxe2x80x9d is an optionally substituted aromatic or non-aromatic, hetero-or carbcycl; and
halo is bromo, chloro or iodo.
Taking the phosphonate antivirals adefovir and cidovir as examples, prodrugs of the invention can be applied as shown in formula PF2:
Representative compounds within formula N-2 include:
2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethyl ester
3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid iodomethyl ester,
2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl iodide
20 Iodomethyl 1,3-bis(N-benzyloxycarbonyl-L-valyloxy)-2-propyl carbonate,
Iodomethyl 2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionate,
Iodomethyl 2-N-benzyloxycarbonyl-L-valyloxy)-DL-propionate.
Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)isobutyrate.
Iodomethyl 2-N-bezyloxycarbanyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate.
Iodomethyl 2O-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate
Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy)benzoate.
Iodomethyl 5-(N-CBz-L-valyloxy)-2,2 dimethylvalerate
2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate
4-(N-CBz-L-valyloxy) butyric acid iodomethyl ester
Iodomethyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate
Iodomethyl-3-(N-benzyloxycarbonyl-L-valyloxy)-propionate
1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl carbonate
3-(N-benzyloxycarbonyl-L-valyloxy)-2,2dimethylpropyl iodomethyl carbonate
Iodomethyl 3,4di-(N-CBZ-L-valyloxy)hydrocinnamate
3-(N-CBZ-L-valyloxy)phenyl iodomethyl carbonate
Iodomethyl 2-(N-CBZ-L-valyloxy)phenylacetate
Iodomethyl 4-(N-CBZ-L-valyloxy)phenylacetate
Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate
Iodomethyl 4-(-benzyloxycarbonyl-L-valyloxy)cyclohexanoate.
Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate
2-(N-(iodomethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl -L-valyloxy)-propane
1-(2-N-CBz-L-valyloxyethyl)-6oxo-1,6-dihydro-pyrdine-3-carboxylic acid iodomethyl ester
Iodomethyl 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate
Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid
2,2-dimethyl-3-(N-Boc-L-isoleucyloxy)propionic acid iodomethyl ester
3,3-bis (N-CBz-L-isoleucyloxymethyl)-propionic acid iodomethyl ester,
2-(N-CBz-L-isoleucyloxy)ethoxycarbonyloxymethyl iodide
Iodomethyl 1,3-bis(-benzyloxycarbonyl-L-isoleucyloxy)-2-propyl carbonate,
Iodomethyl 2-methyl-2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)propionate,
Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)-DL-propionate.
Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)isobutyrate.
Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)-3-methyl-(S)-(+)-butyrate.
Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)-2-phenyl-DL-acetate
Iodomethyl 4-(-benzyloxycarbonyl-L-isoleucyloxy)benzoate.
Iodomethyl 5-(N-CBz-L-isoleucyloxy)-2,2-dimethylvalerate
2-(N-CBz-L-isoleucyloxy)-ethyl iodomethyl carbonate
4-(N-CBz-L-isoleucyloxy) butyric acid iodomethyl ester
Iodomethyl-3-(N-benzyloxycarbonyl-L-isoleucyloxy)-benzoate
Iodomethyl-3-(N-benzyloxycarbonyl-L-isoleucyloxy)-propionate
1,3-bis(N-tert-butoxycarbonyl-L-isoleucyloxy)-2-propyl 1-iodoethyl carbonate
3-(N-benzyloxycarbonyl-L-isoleucyloxy)-2,2-dimethylpropyl iodomethyl carbonate
Iodomethyl 3,4-di-(N-CBz-L-isoleucyloxy)hydrocinnamate
3-(N-CBz-L-isoleucyloxy)phenyl iodomethyl carbonate
Iodomethyl 2-(N-CBz-L-isoleucyloxy)phenylacetate
Iodomethyl 4-(N-CBz-L-isoleucyloxy)phenylacetate
Iodomethyl 4-(2-N-benzyloxycarbonyl-L-isoleucyloxyethyl)benzoate
Iodomethyl 4-benzyloxycarbonyl-L-isoleucyloxy)cyclohexanoate,
Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-ethyl butyrate,
2-(N-(iodomethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl -L-isoleucyloxy)-propane,
1-(2-N-CBz-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid iodomethyl ester
iodomethyl 5-[(N-benzyloxycarbonyl-L-isoleucyloxy)methyl]-2-furoate iodomethyl 4-(2-N-benzyloxycarbonyl-L-isoleucyloxyethoxy)-benzoic acid
and the corresponding chloro analogues.
Further aspects of the invention include the use of intermediate compounds, such as those of the formula N-1, N-2, IIcxe2x80x2, IIaxe2x80x2 VII, the free or activated acid precursors of formula Ia, IIe, IId, IIf etc in the preparation of a pharmaceutical prodrug.
The invention further provides pharmaceutical compositions comprising the compounds of the invention and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods of medical treatment or prophylaxis comprising the administration of a compound of the invention to a human or animal suffering from or prone to the ailment to which the respective Drug is applicable.
Representative drugs having carboxyl functional groups include; angiotensin-converting enzyme inhibitors such as alecapril, captopril, 1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-1,3-duhydro-2S-indole-2-carboxylic acid, enalaprilic acid, lisinopril, N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine, pivopril, (2R, 4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4 -thiazolidinecarboxylic acid, (S)benzamido-4-oxo-6-phenylhexenoyl-2-carboxypyrrolidine, [2S-1[R*(R*))]] 2xcex1, 3xcex1xcex2, 7xcex1xcex2]-1[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid, [3S-1[R*(R*))]], 3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolone carboxylic acid and tiopronin; cephalosporin antibiotics such as cefaclor, cefadroxil, cefamandoie, cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone, cefmenoxime, cefmetazole, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole, cefpirome, cefroxadine, cefsulodin, cefpiramide, ceftazidime, ceftezole, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephanone, cephradine and latamoxef; pcnicillins such as amoxycillin, ampicillin, apalcillin, azidocillin, azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, methicillin, mezlocillin, nafcillin, oxacillin, phenethicillin, piperazillin, sulbenicllin, temocillin and ticarcillin; non-steroidal antiinflamnatory agents such as acametacin, alclofenac, alninoprofen, aspirin (acetylsalicylic acid), 4-biphenylacetic acid, bucloxic acid, carprofen, cinchofen, cinmetacin, clometacin, clonixin, diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid, fenoprofen, ferobufen, flufenaniic acid, flufenisal, flurbiprofin, fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid, naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin, pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid, sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin and zopemirac; prostaglandins such as ciprostene, 16-deoxy-16-hydroxy-16-vinyl prostaglandin E216, 16-dimethylprostaglandin E2, epoprostostenol, meteneprost, nileprost, prostacyclin, prostaglandins E1, E2, or F2xcex1 and thromboxane A2; quinolone antibiotics such as acrosoxacin, cinoxacin, ciprofloxacin, enoxacin, flumequine, naladixic acid, norfloxacin, ofloxacin, oxoljnc acid, pefloxacin, pipemidic acid and piromidic acid.
Representative drugs containing amine groups include: acebutalol, albuterol, alprenolol, atenolol, bunolol, butopamine, butoxamine, carbuterol, cartelolol, colterol, deterenol, dexpropanolol, diacetolol, dobutamine, exaprolol, exprenolol, fenoterol, fenyripol, labotolol, levobunolol, metolol, metaproterenol, metoprolol, nadolol, pamatolol, penbutalol, pindolol, pirbuterol, practolol, prenalterol, primidolol, prizidilol, procaterol, propanolol, quinterenol, rimiterol, ritodrine, solotol, soterenol, sulfiniolol, sulfinterol, sulictidil, tazaolol, terbutaline, timolol, tiprenolol, tipridil, tolamolol, thiabendazole. albendazole, albutoin, alinidine, alizapride, amiloride, aminorex, aprinocid, cambendazole, cimetidine, clonidine, cyclobenzadole, etintidine, fenbendazole, fenmetazole, flubendazole, fludorex, lobendazole, mebendazole, metazoline, nocodazole, oxfendazole, oxibendazole, oxmetidine, parbendazole, ranitidine, tetrahydrazoline, tiamenidine, tinazoline, tiotidine, tolazoline, tramazoline, xylometazoline, dimethoxyphenethylamine, N-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1 -yl]acetyl-3(R)-methyl-xcex2-alanine adrenolone, aletamine, amidephrine, amphetamine, aspartame, bamethan, betahistine, clorprenaline, chlorternine, dopamine, ephrinephrine etryptamine, fenfluramine, methyldopamine, norepinephrine, tocainide enviroxime, nifedipine, nimodipine, triamterene, norfloxacin and similar compounds such as pipedemic acid, 1-ethyl-6-fluoro-1,4-dihydro4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylic acid.
A favoured amine drug, [[3(R)-2-piperidin-4-ylethyl)-2-oxopiperidinyl]acetyl]-3(R)-methyl-xcex2-alanine (also known as L-734,217) has the formula: 
A further preferred amino drug are the bicyclam anti HIV agents, such as AMD 3100: 
Representative drags containing hydroxy groups include:
steroidal hormones such as allylestrenol, cingestol, dehydroepiandrosteron, dienostrol, diethylstilbestrol, dimethisteron, ethyneron, ethynodiol estradiol, estron, ethinyl estradiol, ethisteron, lynestrenol, mestranol, methyl testosterone, norethindron, norgestrel, norvinsteron, oxogeston, quinestrol, testosteron and tigestol;
tranquilizers such as dofexazepam, hydroxyzin, lorazepam and oxazepam;
neuroleptics such as acetophenazine, carphenazine, fluphenazine, perphenyzine and piperaetazine;
cytostatics such as aclarubicin, daunorabicin, dihydro-5-azacytidine. doxorubicin, epirubicin, estramustin, etoposide, 7-hydroxychlorpromazin, neplanocin A, pentostatin, podophyllotoxin, vinblastin, vincristin, vindesin;
hormones and hormone antagonists such as buserilin, gonadoliberin; icatibrant and leuprorelin acetate;
antihistamines such as terphenadine;
analgesics such as diflunisal, naproxol, paracetamol, salicylamide and salicyclic acid; antibiotics such as azidamphenicol, cefamandol chloramphenicol, clavulanic acid, clindamycin, comptothecin, demeclocyclin, doxycyclin, imipenem, latamoxef, novobiocin, oleandomycin, oxytetracyclin, tetracyclin and thiamenicol;
prostaglandins such as arbaprostil, carboprost and prostacydin;
antidepressives such as 8-hydroxychlorimipramine and 2-hydroxyirnipiramine;
antihypertonics such as sotarol and fenoldopam;
anticholinerogenics such as biperidine, carbidopa, procyclidin and trihexyphenidal; antiallergenics such as cromolyn;
glucocorticoids such as betamethasone, budenosid, clilorprednison, clobetasol, clobetasone, corticosteron, cortisone, cortodexon, dexamethason, flucortolon, fludrocortisone, flumethasone, flunisolid, fluprednisolon, flurandrenolide, flurandrenolon acetonide, hydrocortisone, meprednisone, methylpresnisolon, paramethasone, prednisolon, prednisol, triascinolon and triamcinolon acetonide;
narcotic agonists and antagonists such as apomorphine, buprenorphine, butorphanol, codein, cyclazocin, hydromorphon, ketobemidon, levallorphan, levorphanol, metazocin, morphine, nalbuphin, nalmefen, naloxon, nalorphine, naltrexon, oxycodon, oxyrmorphon and pentazocin;
stimulants such asmazindol and pseudoephidrine;
anaesthetics such as hydroxydion and propofol; xcex2-receptor blockers such as acebutolol, albuterol, alprenolol, atenolol, betazolol, bucindolol, cartelolol, celiprolol, cetamolol, labetalol, levobunelol, metoprolol, metipranolol, nadolol, oxyprenolol, pindolol, propanolol and timolol; xcex1-sympathoniimetics such as adrenalin, metararniol, midodrin, norfenefin, octapamine, oxedrin, oxilofrin, oximetazolin and phenylefrin; xcex2-sympathomirnetics such as bamethan, clenbuterol, fenoterol, hexoprenalin, isoprenalin, isoxsuprin, orciprenalin, reproterol, salbutamol and terbutalin;
bronchodilators such as carbuterol, dyphillin, etophyllin, fenoterol, pirbuterol, rimiterol and terbutalin;
cardiotonics such as digitoxin, dobutamin, etilefrin and prenalterol;
antimycotics such as amphotericin B, chiorphenesin, nystatin and perimycin;
anticoagulants such as acenocoumarol, dicoumarol, phenprocoumon and warfarin;
vasodilators such as bamethan, dipyrimadol, diprophyllin, isoxsuprin, vincamin and xantinol nicotinate;
antihypocholesteremics such as compactin, eptastatin, mevinolin and simvastatin;
miscellaneous drugs such as bromperidol (a-ntipsychotic), dithranol psorasis) ergotamine (migraine) ivermectin (antiheliinthic), metronidazole and secnizadole (antiprotozoals), nandrolon (anabolic), propafenon and quinadine (antiarythmics), srotonin (neurotransmitter) and silybin (hepatic disturbance).
The above mentioned monohydric nucleosides are an example of the prodrugs of the invention applied to chain hydroxy functions, typically the 5xe2x80x2 hydroxy function of the (pseudo)saccharide moiety of the nucleoside. However, the fatty acid free aspect of the invention is not limited to the monohydric nucleosides disclosed above, but is also applicable to L and D-nucleosides bearing di, tri and tetrahyric (pseudo)saccharides, such as those of the formula N-3: 
where
B is a natural or unnatural nucleotide base,
RN1 is O or xe2x80x94CH2xe2x80x94, S
RN2 and RN3 are each H or RN2 is methylene or xe2x80x94CH(OH)xe2x80x94 and RN5 is a bond thereto, or RN2 and RN5 together are a bond;
n is 0 or 1;
one of RN3 and RN4 comprises a linker-R2 structure such as those of formulae IIaa, IIxe2x80x2aa, IIcxe2x80x2, IIexe2x80x2, IIf*, idxe2x80x2 and the other is hydrogen or a further linker-R2 structure.
An alternative group drugs to which the invention is applicable includes those of formula N-3a: 
where B, NR3 and NR4 are as defined above.
Alternative group of drugs within the scope of the invention has the formula N-3b: 
where B, RN3and RN4 are as defined above and RN6 is fluoro and RN7 is hydrogen or RN6 and RN7 are both fluoro or RN6 and RN7 together define an exo-methenyl group. The preferred base is guanine in this alternative.
A further group of nucleosides within the scope of the invention has the formula N-3c 
where B, RN3 and RN4 are as defined above, RN8 and RN9 are fluoro (or one of them is fluoro and the other is hydrogen) or RN8 and RN9 together define exomethenyl or exomethenyl mono or di-subsituted with fluoro. These nucleosides have anticancer activity.
The invention is also applicable to other nucleosides having at least two hydroxy groups, but outside the scope of formula N-3a-c, for instance, 9-[3,3-dihydroxymethyl-4-hydroxy-but-1-yl]guanine as described in WO 95/22330 and 9-[4-hydroxy-(2-hydroxymethyl)butyl]guanine as described in EP 343 133. The invention is applicable to both L and D stereo forms of the various nucleoside analogues
The compounds of the invention, especially cytosine or guanine derivatives where NR1 is oxygen, n is 1 and NR2 and NR5 define a ring are also active against certain retroviral infections, notably SIV, HIV-1 and HIV-2, and Hepatitis B virs. The compounds of the invention, especially cytosinc, guanosine or 6-methoxyguanosine derivatives wherein NR1 is oxygen, n is 0 and NR2 and NR5 define an arabinose ring are potent anticancer compounds.
The compounds of the invention, especially derivatives comprising a 1,2,4-triazole-3-carboxamide base, where NR1 is O, NR2 is xe2x80x94CH(OH)xe2x80x94, NR3 is a bond thereto and n is 0 (ribavirin) are expected to be active against hepatitis C virus (HCV). Compounds comprising a substituted benzimidazole base, where NR1 is O, NR2 is xe2x80x94CH(OH)xe2x80x94, NR5 is a bond thereto and n is 0 (for instance Glaxo Wellcome""s 1263W94 where the base is 2-isopropylamin-5,6-dichloro-benzimidazol-3-yl) are expected to be active against CMV. Compounds comprising an adenine base, where NR1 is O, NR2 is xe2x80x94CH(OH)xe2x80x94, NR5 is a bond thereto and n is 0 (vidarabine) are expected to be active against HSV encephalitis. Compounds comprising a 2chloroadenine base with a 2xe2x80x2-deoxyribose sugar are expected to have anticancer activity.
The nucleoside derivatives of the invention are particularly useful for guanine nucleoside and analogues which tend to have poorer uptake than pyrimidine nucleosides. Accordingly B is preferably guanine or a guanine derivative.
A group of hydroxy bearing drugs which are particularly amenable to the prodrugs of the invention are the ring hydroxy compounds. By ring hydroxy is meant that the hydroxy function to which the prodrug of the invention is bound is bonded directly onto an aromatic or non-aromatic, heterocyclic or carbocyclic ring structure.
Examples of ring hydroxy compounds include the cyclic urea HIV protease inhibitors, such as those described in WO 9843969, W09820008, and WO 9419329. Representative protease inhibitors include: 
Some examples of phenolic ring hydroxy compounds include the PETT NNRTI discussed below or the compound described in J Med Chem 35 3467 (1992): 
Pancratistatin described in Anticancer Drug Design 10: 243 and 299 (1995) and Bioorg Med Chem Lett 6 157 1996; 
has both phenolic and carbocyclic ring hydroxy functions A further useful drug with a combination of phenolic and carbocyclic hydroxy functions is etoposide: 
as described in Bioorg Med Chem Lett 4 2567 (1994) and Clinical Cancer Res 1 105 1995.
Representative phosphorous containing drugs include phosfestrol, (E)-(xcex1,xcex2-diethyl-4,4xe2x80x2-stilbenylen)bis(dihydrogenphosphate) and cytostatic metabolites such as phosphorylated cytarabin or gemcitabin,
Other phosphonates include antiviral nucleoside or nucleotide analogues such as PMEA, HPMPC, PMPA and the like or phosphates such as the monophosphates of those nucleoside analogues which require phosphorylation for activity, such as ACV AZT, ddI, ddC, PCV, GCV, BVDU, FMAU, 3TC, FTC etc. As described above, certain mixed amino acid/fatty acid acyloxyalkylphosphonates are described in our copending application PCT SE97 001903 and it should be thus appreciated that the prodrugs of the present invention are fatty acyl-free and/or apply the novel linkers defined herein in the phosphonate nucleotide field.
Taking the phosphonate antivirals adefovir and cidovir as examples, prodrugs of the invention can be applied as shown in Formula PF2: 
where
R2 is the acyl residue of an aliphatic amino acid,
R4L and R4Lxe2x80x2 independently H, C1-3 alkyl, C3-6cycloalkyl, C1-3alkyl-C1C6cycloalkyl phenyl or benzyl,
R4R and R4Rxe2x80x2 are independently H, C1-3 alkyl or phenyl
qI is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR4xe2x80x94 or xe2x80x94Oxe2x80x94
R4 is H or C1-3alkyl;
R4 is H or C1-3alkyl
ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle;
base is a natural or unnatural nucleotide base, especially guanine, adenine or cystosine, Rf3 is H or a further structure of the formula IIxe2x80x3b and Rf4 is H or CH2OH.
Currently favoured values in formula PF2 include: R3R and R3Rxe2x80x2 are preferably H and/or R3L and R3Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94or more preferably a bond. Preferably qr is 1 or m ore preferably 0.
Thus a preferred group of phosphonate antivirals within the scope of the invention include:
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl) ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-(L-valyloxy)propionyloxymethyl) ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-(L-valyloxy)-3-methyl-(S)-(+) -butyryloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-L-valyloxy) -DL-propionyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(5-(L-valyloxy)-2,2 -dimethylvaleryloxymethyl)ester,
9-[(2-phosphonomethoxy)ethyl]adenine, mono-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl) ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono[4-L-valyloxy)-butanoyloxymethyl]ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(4-(L-valyloxy) benzoyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(3-(3,4di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(4N-valyloxy)cyclohexanoyloxymethyl) ester
9-[2-phosphonomethoxy)ethyl]adenine, mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
9-[2-phosphonomethoxy)ethyl]adenine, mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-L-isoleucyloxymethyl)propionyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono(2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono[4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
9-[2-phosphonomethoxy)ethyl]adenine, mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
9-[2-phospbonomethoxy)ethyl]adenine, mono-(4-N-isoleucyloxy)cyclohexanoyloxymethyl)ester
9-[2-phosphonomethoxy)ethyl]adenine, mono-(1-isoleucyloxy-2-methylpropane-2-amninocarbonyloxymethyl)ester
9-[2-phosphonomethoxy)ethyl]adenine, mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
the corresponding big esters and pharmaceutically acceptable salts thereof. A further preferred group comprises the corresponding derivatives of PMPA and HPMPC.
A further group of phosphorous containing antivirals amenable to the invention include foscarnet (phosphonoformate) and PAA (phosphonoacetate). Taking foscamet as an example: 
it will be apparent that linkers such as those of formula IId or IIxe2x80x2d can be applied to the carboxy function. Preferably, however, or additionally, one or two linkers of formula IIb, IIxe2x80x2b, IIe, IIxe2x80x2e or especially IIxe2x80x3b can be applied to the phosphonate hydroxy functions to define compounds such as: 
Thus a preferred group of compounds comprises foscamet derivatives of the formula PF1: 
where
R2 is the acyl residue of an aliphatic amino acid,
R4Land R4Lxe2x80x2 are independently H, C1-3 alkyl, C3-6cycloalkyl, C1-3alkyl-C1C6cycloalkyl phenyl or benzyl,
R4R and R4Rxe2x80x2 are independently H, C1-3 alkyl or phenyl ql is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR4xe2x80x94 or xe2x80x94Oxe2x80x94
R4 is H or C1-3alkyl;
ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and Rf1 is H or a further ester of formula IIxe2x80x3b and Rf2 is H or a conventional pharmaceutically acceptable ester.
Currently favoured values in Formula PF1 include: R4R and R4Rxe2x80x2 are preferably H and/or R4L and R4Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94 or more preferably a bond. Preferably qr is 1 or more preferably 0.1f Rf1 is a further ester it is convenient if it is identical to other linker-R2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters.
A favoured group of compounds within formula PF1 include:
phosphonoformic acid, mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl)ester,
phosphonoformic acid, mono(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
phosphonoformic acid, mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
phosphonoformic acid, mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
phosphonoformic acid, mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
phosphonoformic acid, mono(2-L-valyloxy)-DL-propionyloxymethyl)ester,
phosphonoformic acid, mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
phosphonoformic acid, mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl)ester,
phosphonoformic acid, mono[4-(L-valyloxy)-butanoyloxymethyl]ester,
phosphonofornic acid, mono-(4-(L-valyloxy)benzoyloxymethyl)ester,
phosphonoformic acid, mono-(3-(3,4-di-(L-valyloxy)phenyl) propionyloxymethyl)ester,
phosphonoformic acid, mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
phosphonoformic acid, mono-(4N-valyloxy)cyclohexanoyloxymethyl)ester
phosphonoformic acid, mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
phosphonoformic acid, mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
phosphonoformic acid, mono(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
phosphonoformic acid, mono(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl)ester,
phosphonoformic acid, mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
phosphonoformic acid, mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
phosphonoformic acid, mono((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
phosphonoformic acid, mono(2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
phosphonoformic acid, mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
phosphonoformic acid, mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl)ester,
phosphonoformic acid, mono[4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
phosphonofornic acid, mono-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
phosphonoformic acid, mono-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl)ester,
phosphonoformic acid, mono(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
phosphonoformic acid, mono-(4-isoleucyloxy)cyclohexanoyloxymethyl)ester
phosphonoformic acid, mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
phosphonoformic acid, mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
the corresponding bis esters, the corresponding compounds additionally bearing a C-ethyl esters, and pharmaceutically acceptable salts thereof.
A further class of phosphonates which are amenable to the invention and which share a structural similarity with phosphonoformic are the xcex2-phosphonocarboxylic acid famesyl protein transferase inhibitors, especially those of the of the formula PF4: 
where
RF1 is H or a further structure of formula IIxe2x80x3b
Rf2 is H or a conventional pharmaceutically acceptable ester,
Rf3 is a polyunsaturated, branched C6-22 alkyl,
R2 is the acyl residue of an aliphatic amino acid,
R4Land R4Lxe2x80x2 are independently H, C1-3 alkyl, C3-6cycloalkyl, C1-3alkyl-C1C6cycloalkyl phenyl or benzyl,
R4R and R4Rxe2x80x2 are independently H, C1-3 alkyl or phenyl ql is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR4xe2x80x94 or xe2x80x94Oxe2x80x94
R4 is H or C1-3alkyl;
ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle.
Currently favoured values in Formula PF4 include: R4R and R4Rxe2x80x2 are preferably H and/or R4L and R4Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94 or more preferably a bond. Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it is convenient if it is identical to other linker-R2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters. A convenient polyunsaturated alkyl Rf3 has the formula: 
Other structurally similar phosponates include xcex1-phosphonosulphonates such as squalene synthase inhibitors of the formula PF5: 
where
RF1 is H or a further structure of formula IIxe2x80x3b
Rf2 is H or a conventional pharmaceutically acceptable ester a further structure of formula IIxe2x80x3b
Rf3 is a polyunsaturated, branched C6-22 alkyl,
R2 is the acyl residue of an aliphatic amino acid,
R4Land R4Lxe2x80x2 are independently H, C1-3 alkyl, C3-6cycloalkyl, C1-3alkyl-C1-C6cycloalkyl phenyl or benzyl,
R4R and R4Rxe2x80x2 are independently H, C1-3 alkyl or phenyl
ql is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR4xe2x80x94 or xe2x80x94Oxe2x80x94
R4 is H or C1-3alkyl;
ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle.
Currently favoured values in Formula PF5 include: R4R and R4Rxe2x80x2 are preferably H and/or R4L and R4Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94 or more preferably a bond. Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it is convenient if it is identical to other linker-R2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters. A convenient polyunsaturated alkyl Rf3 has the formula: 
A particularly preferred group of phosphorous containing drugs are the bisphosphonates active in bone metabolism. Favoured bis-phosphonates have the formula: 
where
X is H, halo, hydroxy; and Y is
a) C1-10 alkyl, optionally substituted with
heterocycle,
xe2x80x94NRaRb, where Ra and Rb are independently hydrogen, C1-6 alkyl or join together to form a 5 to 7 membered ring, optionally containing a further hetero atom,
OH, halo, xe2x80x94S(C1-6 alkyl), phenyl, xe2x80x94C1-7 cycloalkyl, (optionally substituted with xe2x80x94NRaRb or OH);
b) C3-7 cycloalkyl, optionally substituted with
xe2x80x94NRaRb, OH, halo, xe2x80x94S(C1-6 alkyl), phenyl, morpholino or pyridyl;
c) halo;
d) piperidinyl;
e) pyrrolidinyl;
f) xe2x80x94S(C1-6 alkyl), optionally substitued with
xe2x80x94NRaRb, OH, halo or phenyl;
g) xe2x80x94Sxe2x80x94phenyl, optionally substituted with
halo, nitro, C1-6 alkyl, C1-6 alkoxy, trifluormethyl, xe2x80x94CONRaRb or xe2x80x94COOH.
Preferred bis-phosphonates include alendronate (X is hydroxy, Y is NH2CH2CH2CH2xe2x80x94), clodronate (X is chloro, Y is chloro), etidronate (X is hydroxy, Y is CH3xe2x80x94), pamidronate (X is hydroxy, Y is NH2CH2CH2xe2x80x94), ibandronate (X is hydroxy, Y is N (CH2CH2CH2CH2CH3)(CH3)CH2CH2xe2x80x94), tiludronate (X is H, Y is 4chlorophenylthio-), risedronate (X is hydroxy, Y is 3-pyridinylmethylene-) and zoledronate (X is hydroxy, Y is (2-(1H-imidazol-1-yl)methylene-)
Taking alendronate as an example: 
it will be apparent that the drug contains several accessible functions (viz the hydroxy group at position 1, the amino group at position 4 and two esterifiable hydroxy groups on each phosphorous. Prodrugs in accordance with the invention can thus be derivatised on one or more of these functions. For instance a linker such as those of Formula IIa above, for instance when T is a bond or xe2x80x94Oxe2x80x94 and V is a bond can be esterified to the 1-hydroxy position or amide-bonded to the 4-amino position. In a favoured embodiment of the invention, however, the prodrugs of the invention are derivatised to the phosphonate groups.
Thus one to three linker structures of formula IIe, IIxe2x80x2e, Va, Vb or most preferably IIxe2x80x2b can be esterified to one or both of the phosphonates, especially one such linker structure on each phosphonate.
Preferred compounds within this bis-phosphonate aspect of the invention thus include those of the formula A1: 
wherein YY and XX have the following values:
wherein amino groups on YY can be optionally substituted with conventional pharmaceutically acceptable amide groups such as xe2x80x94C(xe2x95x90O)C1-6alkyl or an aminoacyl or peptidyl derivative, as described in WO 96/31227; and wherein at least one of Ra1-Ra4 is a structure of the formula 
where
R2 is the acyl residue of an aliphatic amino acid,
R4Land R4Lxe2x80x2 are independently H, C1-3 alkyl, C3-6cycloalkyl, C1-3alkyl-C1C6cycloalkyl phenyl or benzyl,
R4R and R4Rxe2x80x2 are independently H or C1-3 alkyl
ql is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR4xe2x80x94 or xe2x80x94Oxe2x80x94
R4 is H or C1-3alkyl;
ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle;
and the remainder of Ra1-4 are hydrogen or conventional pharmaceutically acceptable esters.
In formula A-1, R4R and R4Rxe2x80x2 are preferably H and/or R4L and R4Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94 or more preferably a bond. Preferably qr is 1 or more preferably 0.
Favoured compounds thus include;
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-(L-valytoxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-L-valyloxy)-DL-propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, bis [4-(L-valyloxy)-butanoyloxymethyl]ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(4-(L-valyloxy)benzoyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(4-valyloxy)cyclohexanoyloxymethyl)ester
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-L-valyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyi-1-yl)ethylidene-bis phosphonate, di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-((2-(L-valyloxy) -ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, bis [4-(L-valyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(4-(L-valyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(4-valyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate di(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-(-L-valyloxy)-2-phenyl -DL-acetyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-L-valyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, bis[4-(L-valyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(4-(L-valyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(4-valyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
and pharmaceutically acceptable salts thereof.
A further group of favoured compounds include:
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-L-valyloxy)-DL-propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono[4-(L-valyloxy)-butanoyloxymethyl]ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(4-(L-valyloxy)benzoyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(4-valyloxy)cyclohexanoyloxymethyl)ester
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono (2-(L-valyloxy)-3-methyl-(S)-(+)butyryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono (2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono ((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono (2-L-valyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(5-(L-valyloxy)-2,2-diethylvaleryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono[4-(L-valyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(4-(L-valyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonylmethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(4-N-valyloxy)cyclohexanoyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-L-valyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono[4-(L-valyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(4-(L-valyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(4 -valyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
and pharmaceutically acceptable salts thereof.
A ether group of favoured compound include:
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
(4amino-1-butylidine)-bisphosphonate, di(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-(L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
(4amino-1-hydroxybutylidine)-bisphosphonate, di((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di(2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
(4amino-1-hudroxybutylidine)-bisphosphonate, bis[4-(-L-isoleucyloxy)-butanoyloxymethyl]ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(4-valyloxy)cyclohexanoyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di(2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, bis[4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(4-isoleucyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, di-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate di(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-(L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di(2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, bis[4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(4-N-isoleucyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, di-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
and pharmaceutically acceptable salts thereof
A further group of favoured compounds include:
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono(2-L-isoleucyloxy)-DL-propionyloxyinethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono[4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(2-methyl-1 -(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
(4amino-1-hydroxybutylidine)-bisphosphonate, mono-(4-isoleucyloxy)cyclohexanoyloxymethyl)ester
(4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
(4amino-1-hydroxybutylidine)-bisphosphonate, mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
1hydroxy-2-(1H-imidazolyl-1-yl)ethylidenebis phosphonate, mono(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono (2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(1-H-imidazolyl4-yl)ethylidene-bis phosphonate, mono ((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(1-H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono (2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(1H-1-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(5-(D-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(1H-1-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono[4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(1H-1-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(4-isoleucyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl)ester
1-hydroxy-2-(1H--imidazolyl-1-yl)ethylidene-bis phosphonate, mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate mono(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
1-hydroxy-2-pyrid-3-yl)ethylidene bis-phosphonate, mono(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono(2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono[4-(N-CBz-L-isoleucyloxy)-butanoyloxymethyl]ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(4-(L-isoleucyloxy)benzoyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(3-(3,4-di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(4-isoleucyloxy)cyclohexanoyloxymethyl)ester
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(1-isoleucyloxy-2-methylpropane-2-aninocarbonyloxymethyl)ester,
1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine3-carbonyloxyinethyl)ester
and pharmaceutically acceptable salts thereof.
A still further preferred group of prodrugs of the invention are those based on fosinoprilate having the formula PF3: 
where
R2 is the acyl residue of an aliphatic amino acid,
R4L and R4Lxe2x80x2 are independently H, C1-3 alkyl, C3-6-cycloalkyl, C1-3alkyl-C1C6cycloalkyl phenyl or benzyl,
R4R and R4Rxe2x80x2 are independently H or C1-3 alkyl
ql is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR3xe2x80x94 or xe2x80x94Oxe2x80x94
R3 is H or C1-3alkyl;
ring is an optionally substituted aromatic or non-aromatic, hetero- or carbocycle;
and pharmaceutically acceptable salts thereof.
In formula PF3, R4R and R4Rxe2x80x2 are preferably H and/or R4L and R4Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94 or more preferably a bond. Preferably qr is 1 or more preferably 0.
Favoured compounds within formula PF3 thus include
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-([(R)(4-phenylbutyl)phosphinyl]acetyl-L-proline, (2-methyl-2-(L-valyloxy)propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, ((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester,
(4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-L-valyloxy)-DL-propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (S-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, ((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, ((4(L-valyloxy)-butanoyloxymethyl]ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (4(L-valyloxy)benzoyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester,
(4-N-valyloxy)cyclohexanoyloxymethyl)ester
(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)
(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine3-carbonyloxymethyl)
(4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-methyl-2-(L-isoleucyloxy)propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, ((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxymethyl)ester,
(4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (2-L-isoleucyloxy)-DL-propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenyl]butyl)phosphinyl]acetyl]-L-proline, ((2-(L-isoleucyloxy)-ethoxycarbonyloxy)methyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, [4-(L-isoleucyloxy)-butanoyloxymethyl]ester,
(4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (4-(L-isoleucyloxy)benzoyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4phenylbutyl)phosphinyl]acetyl]-L-proline, (3-(3,4di-(L-isoleucyloxy)phenyl)propionyloxymethyl)ester,
(4S)-4-cyclohexyl-1-[[(R)(4phenylbutyl)phosphinyl]acetyl]-L-proline, (2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl)ester,
(4-N-valyloxy)cyclohexanoyloxymethyl)ester
(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)
(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)
and pharmaceutically acceptable salts thereof.
A further phosphonate compound amenable to the prodrugs of the invention are the neutral endopeptidase inhibitors such as CGS-24592 (Novartis), preferably those of the formula PF6: 
Rf2 is H or a conventional pharmaceutically acceptable ester,
R2 is the acyl residue of an aliphatic amino acid,
R4L and R4Lxe2x80x2 are independently H, C1-3 alkyl, C1-6cycloalkyl, C1-3alkyl-C1C6cycloalkyl phenyl or benzyl,
R4R and R4rxe2x80x2 are independently H or C1-3 alkyl
ql is 0-3, qr is 0-3,
T is a bond, xe2x80x94NR4xe2x80x94 or xe2x80x94Oxe2x80x94
R4 is H or C1-3alkyl;
ring is an optionally substituted aromatic or non-aromatic, hetero- or carbocycle.
Currently favoured values in Formula PF6 include: R4R and R4Rxe2x80x2 are preferably H and/or R4L and R4Lxe2x80x2 are preferably ethyl or especially methyl. T is preferably xe2x80x94Oxe2x80x94 or more preferably a bond. Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it is convenient if it is identical to other linker-R2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters.
A further convenient Drug for appying the prodrugs of the invention is the anti-Parkinsonian agent levodopa: 
This drug has four accessible functions for applying the prodrugs of the invention, namely the 3 and 4 hydroxy groups on the phenyl and the amino and carboxy functions on the side chain.
A structure of the formula IIa or IIxe2x80x3b be esterified to one or both of the aromatic hydroxyl functions or amide-bonded to the levodopa amino function. A trifunctional linker of Formula III or Formula IId, can be carbonyl bonded to the levodopa carboxyl function. Such xe2x80x9cblockedxe2x80x9d carboxyl levodopa compounds are conceivably less susceptible to in vivo peripheral decarboxylation than levodopa and may thus allow the diminution or omission of the customarily coadministered decarboxylase inhibitors such as carbidopa.
A further convenient Drug for applying tie prodrugs of the invention is chromoglycate, also known as cromolyn, useful in the treatment of asthma, allergic rhinitis, mastocytosis, ulcerative colitis and inflammatory bowel disease: 
It will be apparent that cromolyn has three accessible functions suitable for applying the prodrugs of the invention. In particular, a linker of the formula IId can be carbonyl linked to either of the carboxy groups. As cromolyn is a symmetric compound it may be advantageous to bond a respective linker to each of the carboxyl groups. Alternatively or additionally, a linker of the formula IIa, IIxe2x80x2a, IId, IIxe2x80x2d such as those wherein T is a bond or xe2x80x94Oxe2x80x94 and V is a bond can be esterified to the hydroxy group depending from the propylene bridge, optionally in conjunction with conventional pharmaceutical esters on the carboxy groups.
A further group of Drugs which are amenable to the prodrugs of the invention are the pain-killer opiates such as morphine: 
Morphine and many of its analogues have a pair of hydroxy functions accessible to the prodrug approach of the invention. For instance a structure of formula IIa wherein T is a bond or xe2x80x94Oxe2x80x94 and V is a bond would be convenient for esterification with the 3 and/or 6 hydroxy groups.
A further convenient group of compounds include the macrolide antibiotics such as erythromycin and roxitromycin and antibacterial glycopeptides such as vancomycin.
A further convenient group of Drugs for applying the prodrugs of the invention are the rifamycin antibiotics: 
wherein the asterisks define the requisite number of aromatic bonds, including
rifampicin (Rais OH, Rb is xe2x80x94CHxe2x95x90N-(4-Nxe2x80x2-methylpiperazine), Rc is hydroxy),
rifamide (Ra is OCH2CONH(C2H5)2, Rb is hydrogen, Rc is hydroxy),
rifamycin B (Ra is xe2x80x94OCH2COOH, Rb is hydrogen, Rc is hydroxy),
rifamycin O(Ra is -1,3-dioxolan-4-on)-2-yl, Rb is hydrogen, Rc is hydroxy),
rifamycin S(Ra is xe2x95x90O, Rb is hydrogen, Rc is xe2x95x90O),
rifamycin SV(Ra is xe2x80x94OH, Rb is hydrogen Rc is xe2x80x94OH),
rifaximin (Ra and Rb together define a structure: 
rifabutinum (Ra and Rb together define a structure: 
It will be apparent that the rifamycins have a number of free hydroxyls and secondary amines available for esterification or amide bonding with respective linker-R2 groups in accordance with the invention such as those of Formula IIxe2x80x2a or Formula IIa above, which linker group is bonded to one of said hydroxy or amino groups.
A further group of Drugs which are amenable to the prodrugs of the invention is the cephalosporin antibiotics: 
Representative cephalosporins include:
cefpodoxime (Ra is [(2-amino4-thiazolyl)(methoximino)acetyl]amino-, Rb is H, Rc is ethyl),
cefaclor (Ra is aminophenylacetylamino, Rb is H, Rc is chloro),
cefadroxil (Ra is [amino-(4-hydroxyphenyl)acetyl]amino, Rb is H, Rc is methyl);
cefamandole (Ra is [amino-(4hydroxyphenyl)acetyl]amino, Rb is H, Rc is [1-methyl-1H-tetrazol-5-yl)thio]methyl);
cefatrizine, (Ra is is [amino-(4hydroxyphenyl)acetyl]amino, Rb is H, Rc is [1H-1,2,3-triazol-4-ylthio]methyl);
cefazedone (Ra is [(3,5-dichloro-4-oxo-1(4H)-pyridinyl)acetyl]amino, Rb is H, Rc is [(5-methyl-1,3,4-thiadiazol-2-ylthio]methyl),
cefazolin (Ra is (1H-tetrazol-1-ylacetyl)-amino Rb is H, Rc is [(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl,
cefbuparazone (Ra is [2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxy-1-oxobutyl]amino, Rb is OCH3, Rc is [(1-methyl-1H-tetrazoly-5yl)thio]methyl,
cefixime Ra is [(2-amino-4-thiozolyl)[carboxymethoxy)mino]acetyl]amino, Rb is H, Rc is xe2x80x94CHxe2x95x90CH2),
cefmonoxime, (Ra is [(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino, Rb is h, rc is [(1-methyl-1H-tetrazol-5-yl)thio]amethyl),
cefmetazole ([[(cyanomethyl)thio]acetyl]amino, Rb is H, Rc is [1-methyl-1H-tetrazol-5-yl)thio]methyl),
cefminox (Ra is [[(2-amino-2-carboxyethyl)thio]acetyl]amino, Rb is OCH3, Rc is [1-methyl-1H-1-tetrazol-5-yl)thio]methyl),
cefodoxime (Ra is [(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino, Rb is H, Rc is [[5-(carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl),
cefonicid (Ra is (hydroxyphenylacetyl)amino, Rb is H, Rc is [[1-8sulfomethyl)-1H-tetrazol-5-y]thio]methyl),
cefoperazone (Ra is [[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino, Rb is H, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl),
ceforanide (Ra is [[2-(amninomethyl)phenyl]acetyl]amino, Rb is H, Rc is [[1-(carboxymethyl)-1H-tetrazol-5-yl]thio]methyl),
cefotaxime (Ra is 1(2-amino-4thiazolyl)(methoxyimino)acetyl]amino, Rb is H, Rc is (acetyloxy)methyl),
cefotetan (Ra is [[4-(2-amino-1-carboxy-2-oxoethylidine)-1,3-dithietan-2-yl]carbonyl]amino, Rb is OCH3, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl),
cefotiam (Ra is [(2-amino-4-thiazolyl)acetyl]amino, Rb is H, Rc is [[1-[2-(dimethylamino)ethyl]- H-tetrazol-5-yl]thio]methyl),
cefoxitin (Ra is (2-thienylacetyl)amino, Rb is OCH3, Rc is [aminocarbonyl)oxy]methyl),
cefpimizole (a is [[[(5-carboxy-1H-imidazol-4-yl)carbonyl]amino]phenylacetyl]amino, Rb is H, Rc is (4xe2x80x2-(2-sulfoethyl)pyridinium)methyl hydroxide inner salt,
cefpiramide (Ra is [[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino, Rb is H, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl),
cefroxadine (Ra is (amino-1,4-cyclohexadien-1-yl-acety])amino, Rb is H, Rc is OCH3),
cefsulodin (Ra is (phenylsulfoacetyl)amino, Rb is H, Rc is (4xe2x80x2-carbamoyl pyridinium)methyl hydroxide inner salt),
ceftazidime (Ra is [(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino, Rb is H, Rc is pyridiniummethyl hydrochloride inner salt),
cefteram (Ra is [(2-amino-4-thiazolyl)methoxyimino)acetyl]amino, Rb is H, Rc is (5-methyl-2H-tetrazol-2-yl)methyl),
ceftezole (Ra is (1H-1-tetrazol-1-ylacetyl)amino, Rb is (1,3,4-thiadiazol-2-ylthio)methyl),
ceftibuten (Ra is [2-(2-amino-4-thiazoly-1)-4carboxy-1-oxo-2-butenyl]amino, Rb is H, Rc is H)
ceftiofur (Ra is [(2-amino-4-thiazoyl)(methoxyimino)acetyl]amino, Rb is H, Rc is [(2-furanylcarbonyl)thio]methyl),
ceftizoxime (Ra is [(2-amino-4thiazolyl)(methoxyimino)acetyl]amino, Rb is H, Rc is H),
ceftriaxone (Ra is [(2-amino-4-thiazolyl)methoxyimino)acetyl]amino, Rb is H, Rc is [1,2,5,6-tetrahydro-2-methyl-5,6dioxo-1,2,4-triazin-3-yl)thio]methyl),
cefuroxime (Ra is 2-furanyl(methoxyimino)acetyl]amino, Rb is H, Rc is [(aminocarbonyl)oxy]methyl),
cefuzonam (Ra is 1[(2-amino-4thiazolyl)(methoxyimino)acety1]amino, Rb is H, Rc is (1,2,3-thiadiazol-5-ylthio)methyl),
cephacetrile (Ra is (cyanocetyl)amino, Rb is H, Rc is (acetyloxy)methyl),
cephalexin (Ra is (aminophenylacetyl)amino, Rb is H, Rc is methyl),
cephaloglycin (Ra is (aminophenylacetyl)amino, Rb is H, Rc is (acetyloxy)methyl),
cephaloridine (Ra is (2-thienylacetyl)amino, Rb is H, Rc is pyridinium methyl hydroxide inner salt),
cephalosporin C (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is H, Rc is (acetyloxy)methyl),
cephalothin (Ra is (2-thienylacetyl)amino, Rb is H, Rc is (acetyloxy)methyl),
cephamycin A (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is OCH3 Rc is xe2x80x94CH2OCOC(OCH3)xe2x95x90CHxe2x80x94(4-oxysulphyl)phenyl),
cephamycin B (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is OCH3 Rc is xe2x80x94CH2OCOCC(OCH3)xe2x95x90CH-(4hydroxy)phenyl),
cephamycin C (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is OCH, Rc is xe2x80x94CH2OCONH3)
cephapirin (Ra is [(4-pyridinylthio)acetyl]amino, Rb is H, Rc is (acetyloxy)methyl),
cephradine (Ra is (amino-1,4-cyclohexadien-1-yl-acetyl)amino, Rb is H, Rc is CH3).
Common for the above cephalosporins is the presence of a carboxy group at the 2-position which is amenable to derivation with a linker group, in particular those of the Formula III and IIId and IId and IId defined above. The above listed Ra, Rb and Rc groups may also be combined in various permutations and the invention includes prodrugs of all such cephalosporins.
A further group of Drugs which are amenable to the prodrugs of the invention are the anticholinesterases such as tacrine: 
where R is H or OH. It will be apparent that the tacrine itself (Rxe2x95x90H) has a free amine group suitable for derivatisation with a linker-R2 group such as those of Formula IIa, for instance when T is a bond or xe2x80x94Oxe2x80x94 and V is a bond. The tacrine metabolite (Rxe2x95x90OH), which is also active in vivo has an additional hydroxy function which can alternatively or additionally be derivatised with a linker such as those of Formula IIa, for instance when T is a bond or xe2x80x94Oxe2x80x94 and V is a bond.
A further group of Drugs which are amenable to the prodrugs of the invention are the sulphonamide diuretics such as furosemide: 
It will be apparent that furosemide has a free carboxylic function, a primary amine and a secondary amine amenable to the prodrugs of the invention. In particular an R2 bearing linker, such as those of Formula III, IIIxe2x80x2 or Formula IId. IIxe2x80x2d can be carbonyl linked to the free carboxy function. Alternatively or additionally, an R2 bearing linker, such as those of Formula IIa or IIxe2x80x2a, for instance where T is a bond or xe2x80x94Oxe2x80x94 and V is a bond can be amide bonded to the primary and/or secondary amine groups.
A further group of Drugs amenable to the prodrugs of the invention include the xcex1-1 and xcex2-blocker carvedilol compounds: 
Carvedilol has a free hydroxy function, a secondary hetero cyclic amine and a further secondary amine on the side chain, which are amenable to the prodrugs of the invention, such as those of Formula IIxe2x80x2a, for instance where T is a bond or xe2x80x94Oxe2x80x94 and V is a bond which is in turn linked to the hydroxy and/or the ring amine and/or the side chain amine functions on carvedilol.
A further group of Drugs which are amenable to the prodrngs of the invention are the hypolipaemic statin, such as flustatin or compounds of the formula: 
such as pravastatin (Raxe2x95x90H, Rbxe2x95x90OH, Rcxe2x95x90H ,Rdxe2x95x90OH) and simvastatin (Raxe2x95x90CH3, Rbxe2x95x90CH3, Rc and Rd together define a bond).
Taking simvastatin as an example, it will be apparent that there is a free side chain hydroxyl which is available for linkage with an R2 bearing linker, such as those of Formula IIa, for instance where T is a bond or xe2x80x94Oxe2x80x94 and V is a bond.
The statin pravastatin also bears a corresponding hydroxy function and can be derivatised with a linker in the same fashion. Pravastatin also bears a ring hydroxyl and a further side chain hydroxyl function which can be derivatised with a linker in a corresponding fashion. Pravastatin also bears a carboxyl function which can additionally or alternatively be derivatised with an R2 bearing linker such as those of Formula II, IIIxe2x80x2 or Formula IId, IIdxe2x80x2.
A further group of Drugs which are amenable to the prodrugs of the invention are peptides and pseudopeptides such protease inhibitors including antifibrinolytics like aprotinin or peptidomimetic aspartyl protease inhibitors such as renin inhibitors. Other peptide Drugs include hormones such as vasopressins. Taking vasopressins as an example, peptide Drugs may be cyclic oligopeptides consisting solely of amino acids such as desmopressin or oxytocin, wherein the N and C terminals represent accessible functions for derivatisation in accordance with the invention. Additionally many peptide drugs include amino acids with side chains bearing accessible functions such as arginine, serine or aspartate. Alternatively a peptide Drug, particularly peptidomimetics can be derivatised with non-amino acid structures bearing accessible functions such as somatostatin octreotide.
Useful oligopeptides for derivisation according to the invention include MX 383 an Arg-Gly-Asp analogue useful as an antithrombotic, DADLE (Tyr-D-Ala-Gly-Phe-D-Leu), an encephalin analogue and NISIN.
An exemplary group of protease inhibitors amenable to the invention comprises the HIV protease inhibitors bearing one or more chain hydroxy functions and/or one or more ring hydroxy functions such as the indanolamine terminal group in Mercks indinavir: 
Favoured prodrugs of indinavir in accordance with the invention include
[1-(1S,2R), 5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-butyryloxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl-D-erythro-pentonamide,
A further indanol based HIV protease inhibitors is Novrtis/BMS SDZ PRI 053: 
A further group of HIV protease inhibitors include the hexose derived compounds described in WO 98145330, the contents of which are hereby incorporated by reference. These compounds typically have the general formula I: 
wherein:
Axe2x80x2 and Axe2x80x3 are independently a group of the formula II: 
wherein:
Rxe2x80x2 is H, CH3, C(CH3)2, xe2x80x94OR1, xe2x80x94N(R)2, xe2x80x94N(Ra)ORa or xe2x80x94DP
Rxe2x80x2xe2x80x3 is H, CH3; Ra is H, C1-C3 alkyl;
D is a bond, C1-3 alkylene, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
P is an optionally substituted, mono or bicyclic carbo- or heterocycle;
Rxe2x80x3 is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH2)nDP;
M is a bond or xe2x80x94C(xe2x95x90O)N(Rxe2x80x2xe2x80x3)xe2x80x94;
Q is absent, a bond, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94CH2xe2x80x94;
or Rxe2x80x3 together with Q, M and Rxe2x80x2 define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring;
with the proviso that Rxe2x80x2 is xe2x80x94ORa, xe2x80x94N(CH3)2, xe2x80x94N(Ra)ORa or xe2x80x94DP if M is a bond and Q is absent;
X is H, OH, OCH3;
Y is H, OH, OCH3, but X and Y are not both H;
Zxe2x80x2and Zxe2x80x3 are independently xe2x80x94(CH2)mP where P is as defined above;
and n and m are independently 0,1 or 2,
and pharmaceutically acceptable salts thereof.
Carbocyclic groups for Rxe2x80x2 as xe2x80x94DP and/or Zxe2x80x2/Zxe2x80x3 and/or the optional substituents thereto may be saturated, unsaturated or aromatic and include monocyclic rings such as phenyl, cyclohexenyl, cyclopentenyl, cyclohexanyl, cyclopentanyl, or bicyclic rings such as indanyl, napthyl and the like.
Heterocyclic groups for Rxe2x80x2 as xe2x80x94DP and/or Zxe2x80x2/Zxe2x80x3 and/or the optional substituents thereto may be saturated, unsaturated or aromatic and have 1 to 4 hetero atoms including monocyclic rings such as futryl, thienyl, pyranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrirnidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like or bicyclic rings especially of the above fused to a phenyl ring such as indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothienyl etc. The carbo or heterocyclic ring may be bonded via a carbon or via a hetero atom, typically a nitrogen atom, such as N-piperidyl, N-morpholinyl etc.
Disclosed embodiments of Formula II for the Axe2x80x2/Axe2x80x3 groups of the compounds of formula I include those of the formula IIa: 
where n is 1 or 2 and Rxe2x80x2 is alkyloxy, preferably methyloxy, or those where n is 0 and Rxe2x80x2 is methyl.
Other disclosed groups of formula II include IIb below 
An alternative configuration for the Axe2x80x2/Axe2x80x3 groups of the compounds of the invention includes groups of the formula IIc: 
where Q is a bond, methylene of xe2x80x94C(OH)xe2x80x94 and Rxe2x80x2 is xe2x80x94ORa, xe2x80x94N(Ra)2, xe2x80x94NRaORa, where Ra is H or C1-C3 alkyl, or a carbo- or heterocyclic group including N-piperidine, N-morpholine, N-piperazine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl etc.
A subset of compounds within formula IIc has the formula IId: 
where Rd is hydrogen or methyl (that is a valyl or isoleucyl side chain) and Rc is 
where X is methylene, O, S, Sxe2x95x90O, S(xe2x95x90O3), or NH or Rc is xe2x80x94N(CH3)2, xe2x80x94NHOH, xe2x80x94NHOMe, xe2x80x94NHOEt, xe2x80x94NMeOH, xe2x80x94NMeOMe etc.
In each of formulae IIa, IIb and IIc, Rxe2x80x3 is hydrogen, methyl, ethyl, isopropyl, cycloakyl such as cyclopropyl, cyclobutyl or cyclohexyl, cycloalkenyl, benzyl, carboxacetamide or 4-imidazolylmethy, any of which may be substituted as defined above. Preferred Rxe2x80x3 groups include the side chains found in the natural amino acids, especially those of leucine, asparagine, histidine or proline. The most preferred xe2x80x3 groups for formula IIa, IIb, IIc and IId are the isoleucyl and especially the valyl side chain.
Rxe2x80x2 will vary depending on the nature of Q and/or M, if present, and may for instance be selected from hydrogen, methyl, ethyl, isopropyl, Rc as defined above, valinol, a heterocycle such as pyridyl, thiazole, oxazole, imidazole, N-piperidine, N-morpholine, N-piperazine, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, pyrazinyl, any of which Rxe2x80x2 groups may be substituted as defined for Zxe2x80x2/Zxe2x80x3 below.
Further disclosed Axe2x80x2/Axe2x80x3 groups include those of formula II where Rxe2x80x3, Q, M and Rxe2x80x2 together define an optionally substituted 5 or 6 membered carbo- or heterocylic ring, A preferred group within this definition include groups within formula III: 
where
Rxe2x80x2xe2x80x3 is as defined above,
Rxe2x80x2is H, NR4R4, C(xe2x95x90O)R3, CR3R4 or a monocyclic, optionally substituted carbo- or heterocycle;
R2 is OH, or together with R1 is xe2x95x90O, or if R1 is NR4R4, then R2 may be H;
R3 is H, halo, C1-C3 alkyl OR5, NR4R4;
R4 is H, C1-C3 alkyl;
R5 is H or a pharmaceutically acceptable ester;
R6 is OH, NH2, carbamoyl or carboxy;
R7 is hydrogen, C1-C4 straight or branched alkyl or together with the adjacent carbon atoms forms a fused phenyl or heteroaromatic ring;
Preferred groups of formula III include aminoindanol and 1-amino-azaindan-2-ol, that is moieties of the formulae: 
This aspect of the present invention thus provides compounds of the formula IV: 
where Axe2x80x2, Axe2x80x3, Zxe2x80x2 and Zxe2x80x3 are as defined above, one of Rxxe2x80x2 and Rxxe2x80x3 is H, OH or OCH3 and the other one of Rxxe2x80x2 and Rxxe2x80x3 is a group of the formula xe2x80x94Oxe2x80x94Lxe2x80x94Ry where Ry is the acyl residue of an aliphatic amino acid and L is a bifunctional linker group.
With the expression xe2x80x9cbifunctional linker groupxe2x80x9d is meant a group which bears a function amenable to an acyl bond with the carboxy function of the amino acid derivative Ry and is also able to bond with an hydroxy function at the 3 or 4 position of the alkyl backbone of the structure of formula III. Exemplary L groups include an alkoxy moiety such as xe2x80x94CH3Oxe2x80x94, xe2x80x94CH(CH3)Oxe2x80x94, C(CH3)2Oxe2x80x94 and the like. Other exemplary L groups include an alkoxyalkoxy moiety such as xe2x80x94CH3O-Alk-Oxe2x80x94, xe2x80x94CH(CH3)O-Alk-Oxe2x80x94, C(CH3)2O-Alk-O, where Alk is a C1-C6 branched or straight chain saturated or unsaturated alkylene group, such as methylene, ethylene, 1,1 bismethylethylene and the like. Other exemplary L groups include derivatives of hydroxyalkanoic acids, where the carboxy unction is acylated to the hydroxy function at the 3 or 4 position of the backbone of the structure of formula III, while the hydroxy function is available for acylation with the carboxy function of the amino acid group Ry. Convenient hydroxyalkanoic acids include those derived from xcex1-hydroxy xcfx89-carboxylic acids such as carbonic acid, glycollic acid, hydroxypropanoic acid, hydroxybutyric acid, hydroxyvaleric acid or hydroxycaproic acid.
A number of convenient bifunctional linker groups are described in SE 9801216-4 which is hereby incorporated by reference, and also the disclosure of PCT/SE98/01467, also incorporated herein by reference.
Linkers prepared from xcfx89-hydroxybutyric derivatives are convenient as with these compounds hydrolysis and removal of the Ry group in vivo leaves a reactive terminal radical which will tend to cyclize and prompt the effective release of the mother protease inhibitor. Similarly, linkers of the formula La: 
are convenient as enzymatic or spontaneous hydrolysis of a first of the Ry groups will result in an active terminus able to curl back and attack the acyl linkage to the mother compound thus promoting spontaneous release of the linker fragment. Other convenient linkers along the same principle have the formula Lb or Lc: 
Preferred Ry groups include those derived from L-alanine, L-leucine and especially L-isoleucine and L-valine.
Favoured mother compounds within Formula IV include those of the formula IVA: 
where Rdxe2x80x2 and Rdxe2x80x3 are independently the side chain of an aliphatic L-amino acid, especially those of valyl or isoleucyl, one of Rxxe2x80x2 and Rxxe2x80x3 is hydroxy or hydrogen and the other is xe2x80x94Oxe2x80x94Lxe2x80x94Ry, and Rz and Rzxe2x80x2 are independently H, halo, amino, mercapto, oxo, nitro, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-c6 alkanoyl, C1-C6 alkoxy, thioC1-C6 alkyl, thioC1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, haloC1-C6 alkyl, aminoC1-C6 alkyl, cyano, carboxyl, carbalkoxy, carboxamide, carbamoyl and the like, any of which alkyl moieties being optionally fluoro substituted, or an optionally substituted 5 or 6 membered carbocyclic or heterocyclic ring structure, such as cyclohexanyl, cyclohexenyl, phenyl, furyl, thienyl, pyranyl, pyrrolyl, pyrrolinyl, pyrroidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperdinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like. The ring structure mnay be bonded via a carbon atom or a hetero nitrogen. The ring structure may itself substituted with substituents as defined immediately above.
X ray crystallography indicates that there is significant scope for bulky substitution at Rzxe2x80x2 and/or Rzxe2x80x3 with (optionally substituted) groups such as para-phenyl, para-pyrid-2-yl, para-pyrid-3 yl, para-thien-2-ylyl, parathien-3yl, para-pyrimid-2-y, para-pyrimid-3-yl, para-pyrimid-4-yl and parathiazol-2-yl.
Alternatively or additionally Rzxe2x80x2 and/or Rzxe2x80x3 can compromise a smaller substituent intended for interaction with adjacent portions of the molecule. For instance, an ortho-fluoro group can hydrogen bond with any hydroxy groups present in Axe2x80x2 or Axe2x80x3, thus serving to prevent hydrophobic collapse and/or functioning as a pseudoscaffold. This is best seen with the compounds of Formula IIIB below.
Exemplary compounds within Formula IVA thus include:
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-4-O-(3-(L-valyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-O-(4-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-O-4-(2-(L-valyloxymethyl)benzoyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4- O-(3-(L-valyloxy)propionyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy) hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbanoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoeucyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoeucyloxy)-cis-but-2-enoyl) hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoceucyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoelucyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-isoleuclyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleuclyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-isoleuclyloxymethyl)benzoyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-valytoxy)propionyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethylbenzoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoleucyloxymethyl)benzoyl)hexanediamide,
N1, N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4(L-isoleucyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-isoleuclyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-isoleucyloxymethyl)benzoyl)hexanediamide,
A variant of this aspect of the invention provides compounds generally in accordance with Formula IVA, but wherein one or both rd comprise an isobutyl moiety. The mother compounds of this variant are prepared with the dilactone opening procedure described in PCT/SE98/00622, employing L-tert-leucine methylamide (CAS reg nr. 89226-12-0). These mother compounds are themselves novel and define a further aspect of the invention.
Preferred compounds within thus variant include:
N1,N6-di[(1S)-2,2 dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R, 5R)-2,5-di(4-(thien-3-yl)benyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2,2-diethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoeucyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoeucyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoeucyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucytoxymethyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoelucyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-isoleuelyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleuclyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-isoleuclyloxymethyl)benzoyl)hexanediamide.
An alternative preferred group of compounds of the invention are those of Formula IVB: 
where Rxxe2x80x2, Rxxe2x80x3, Rzxe2x80x2 and Rzxe2x80x3 are as defined above and wherein the ring atom adjacent one or both asterisks is optionally replaced by xe2x80x94Nxe2x80x94 to define a fused cyclopentanylpyridyl ring.
Currently preferred Rzxe2x80x2 and Rzxe2x80x3 groups in Formula IV include ortho halogen, or phenyl, pyridyl, pyrimidyl, thiazolyl or thienyl in the para position relative to the linkage to the benzyloxy linkage. Especially preferred is orthofluoro as this appears to allow a favourable hydrogen bonding interaction with the hydroxy group on the adjacent indanol as depicted in the representative compound denoted IVBxe2x80x2 below: 
Exemplary compounds within Formula IVB thus include:
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)-methyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-valytoxy)pentanoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-fluorobenzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)-methyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)-methyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoleucyloxymethyl)benzoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-(L-isoleucyloxy-(1-methyl)methyloxy)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1R-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide.
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)hexanediamide,
N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(2-(L-isoleucyloxymethyl)benzoyl)hexanediamide.
A still further aspect of the invention provides derivatives of the formula IVC, which compounds are alternative derivatives of the mother compounds of formula IVB: 
where X, Y, Rzxe2x80x2, and Rzxe2x80x3 are as defined above, one of Rxcxe2x80x2 or Rxxe2x80x3cxe2x80x3 is xe2x80x94Oxe2x80x94Lxe2x80x94Rdxe2x80x2 and the other is OH or xe2x80x94Oxe2x80x94Lxe2x80x94Rdxe2x80x3 and the position adjacent the asterisk is occupied by xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94 thereby defining a fused cyclopentanylphenyl or pyridyl ring.
Exemplary compounds within this aspect of the invention include:
N1,N6-di[(1S,2R)-2-(L-valyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-valyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(3-(L-valyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-dibenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(5-(L-valyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(2-(L-valyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-isoleucyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-isoleucyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(3-(L-isoleucyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(5-(L-isoleucyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(2-(L-isoleucyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-valyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-valyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,
N1,N6-di [(1S,2R)-2-(3-(L-valyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(5-(L-valyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R, 4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(2-(L-valyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-isoleucyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(L-isoleucyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(3-(L-isoleucyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(5-(L-isoleucyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(fluorobenzyloxy)-3,4dihydroxy-hexanediamide,
N1,N6di[(1S,2R)-2-(4-(L-isoleucyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
N1,N6-di[(1S,2R)-2-(2-(L-isoleucyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,
A further aspect of the invention provides compounds wherein Axe2x80x2 and Axe2x80x3 differ, preferably by including an amino terminus as depicted in Formula IVA (including the isobutyl variant) and an amino terminus as depicted in Form IVB or IVC below. Methodology for preparing such asymmetric mother compounds is disclosed in PCT/SE98/00622. Representative asymmetric compounds include those of the formula IVbb below: 
where X, Y, Rzxe2x80x2, and Rzxe2x80x3 are as defined above, one of Rxcxe2x80x2 or Rxxe2x80x3cxe2x80x3 is xe2x80x94Oxe2x80x94Lxe2x80x94Rdxe2x80x2 and the other is OH or xe2x80x94Oxe2x80x94Lxe2x80x94Rdxe2x80x3 Raa is H or CH3 and the position adjacent the asterisk is occupied by xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94 thereby defining a fused cyclopentanylphenyl or pyridyl ring.
Favoured mother compounds of formula IVbb include those where Rz and Rzxe2x80x2 are a cyclic group such as phenyl, pyridyl or the thiazolyl with the formula: 
The compounds of formula IVbb (as with indinavir above) have chain hydroxy functions amenable to the invention, but more importantly also have an easily accessible ring hydroxy function on the indanol.
In keeping with the usual practice with retroviral inhibitors it is advantageous to co-administer one to three or more additional antivirals, such as AZT, ddI, ddC, d4T, 3TC, H2G, foscarnet, ritonavir, indinavir, saquinavir, nevirapine, delaviridine, efavirenz, amprenavir, Agouron AG1343 and the like. Such additional antivirals will normally be administered at dosages relative to each other which broadly reflect their respective therapeutic values. Molar ratios of 100:1 to 1:100, especially 25:1 to 1:25, relative to the compound or salt of formula I will often be convenient.
The compounds of the aspect of the invention discussed immediately above invention are generally prepared by alkylation or acylation of the respective mother compounds, which are in turn prepared by the methodology described in PCT/SE98/00622. Aklylation or acylation generally proceeds via an activated derivative. The activated derivative used in an acylation may comprise e.g., the acid halide, acid anhydride, activated acid ester or the acid in the presence of coupling reagent, for example dicyclohexylcarbodiimide, where xe2x80x9cacidxe2x80x9d to a precursor group such as those of the formula PGNHC(Rd)COOxe2x80x94Lxcex1-COOH, where Rd is defined above, PG is a conventional N-protecting group and Lxcex1 is the residue of the linker.
Activated Lxe2x80x94Ry groups wherein L is derived from an hydroxyalkanoic acid are conveniently prepared by esterification of conventionally carboxy protected hydroxyalkanoic acid, such as glycollic acid or lactic acid or more preferably an xcfx89-hydroxyalkanoic acid such as 3-hydroxypropionic acid, 4-hydroxybutyric acid, 5-hydroxypentanoic acid etc with the appropriate N-protected Ry derivative, such as N-Cbz-isoleucine, either as the free acid in conjunction with a coupling agent such as DCC, or activated, for instance to the corresponding acid halide. The carboxy protecting group is removed as is known in the art and the resulting intermediate activated and esterified with the mother compound of formula IV, such as those of formula IVA, IVB or IVC with the methodology described above. The N-protecting group on Ry is then removed by conventional deprotection conditions.
Activated Lxe2x80x94Ry groups wherein L is derived from a cis-alkenoic acid, such as 4-hydroxy-cis-but-2-en are conveniently prepared from the corresponding haloalkanoic acids, such as 4-bromo-cis-but-2-enoic acid which is carboxy protected, for instance with t-butyl prior to conventional esterification under with the appropriately N-protected Ry moiety, sicha N-Cbz-valine. The carboxy protecting group is removed and the free carboxy activated and esterified with the mother compound of formula IV as described above, followed by deprotection of the N-protecting group.
Activated Lxe2x80x94Ry groups wherein L is derived from a 2-hydroxymethylbenzoic acid can be prepared from 2-methylbenzoic acid which is carboxy protected and brominated by conventional techniques. This activated intermediate is esterified with an appropriately N-protected Ry moiety, such as Cbz-valine. This intermediate is carboxy deprotected and esterified with the mother compound of formula IV as described above, followed by deprotection of the Ry N-protecting group.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (John Wiley and Sons, New York, 1981), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Favoured N-protecting groups include formyl, acetyl, allyl, F-moc, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).
Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsiyl, triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like, substituted ethyl ethers such as 1-ethoxymethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such as trityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especially the chloride). Ester hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like.
Useful intermediates for acylation with the mother compounds thus include:
3-N-Boc-L-valyloxypropanoic acid, 3-N-Fmoc-L-valyloxypropanoic acid, 3-N-CBZ-L-valyloxypropanoic acid, 3-N-Boc-L-isoleucyloxypropanoic acid, 3-N-Fmoc-L-isoleucyloxypropanoic acid, 3-N-CBZ-L-isoleucyloxypropanoic acid, 4N-Boc-L-valyloxybutyric acid, 3-N-Fmoc-L-valyloxybutyric acid, 4-N-CBZ-L-valyloxybutyic acid, 4N-Boc-L-isoleucyloxybutyric acid, 3-N-Fmoc-L-isoleucyloxybutyric acid, 3-N-CBZ-L-isoleucyloxybutyric acid and the like;
and the activated derivatives, such as the acid halides.
Still further useful intermediates include precursors, such as;
2-(L-valyloxy)propanoic acid, 2-(N-Boc-L-valyloxy)propanoic acid, 2-(N-Fmoc-L-valyloxy)propanoic acid, 2-(N-CBZ-L-valyloxy)propanoic acid, 2-(L-isoleucyloxy)propanoic acid, 2-N-Boc-L-isoleucyloxy)propanoic acid, N-(Fmoc-L-isoleucyloxy)propanoic acid, N-(CBZ-L-isoleucyloxy)propanoic acid,
2-(L-valyloxy)butyric acid, 2-(N-Boc-L-valyloxy)butyric acid, 2-(N-Fmoc-L-valyloxy)butyric acid, 2-(N-CBZ-L-valyloxy)butyne acid, 2-(L-isoleucyloxy)butyric acid, 2-(N-Boc-L-isoleucyloxy)butyric acid, N-(Fmoc-L-isoleucyloxy)butyric acid, N-(CBZ-L-isoleucyloxy)butyric acid, and the like;
and activated derivatives thereof, such as the acid halides.
Still further novel intermediates include precursors such as:
3-ethoxycarbonyl-2-valyloxy-propionic acid
3-ethoxycarbonyl-2-isoleucyloxy-propionic acid
4-ethoxycarbonyl-2,3-bis-valyloxy-butyric acid
4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyric acid
3-benzyloxycarbonyl-2-valyloxy-propionic acid
3-benzyloxycarbonyl-2-isoleucyloxy-propionic acid
4-benzyloxycarbonyl-2,3-bis-valyloxy-butyric acid
4-benzyloxycarbonyl-2,3-bis-isoleucyloxy-butyric acid, and the like;
particularly those derived from xe2x80x9cnaturalxe2x80x9d configurations such as L-malic and L-tartaric acid, and the corresponding activated derivatives such as the acid halides.
Alkylation of the mother compound of figure IV, for instance when group Lxe2x80x94Ry is derived from an alkoxyamino acid ester, is conveniently done with the corresponding N-protected haloalkoxyamino acid ester. Convenient alkylation intermediates thus include
iodomethyloxy-N-CBz-valyl,
iodomethyloxy-N-Boc-valyl,
iodomethyloxy-N-Fmoc-valyl
iodomethyloxy-N-CBz-isoeucyl,
iodomethyloxy-N-Boc-isoleucyl,
iodomethyloxy-N-Fmoc-isoleucyl,
and corresponding derivatives bearing other N-protecting groups.
Further useful intermediates and methodology for acylation or alkylation of the mother compounds of formula IV are disclosed or suggested in (M132) SE 980216-4 filed Apr. 7, 1998, the contents of which are specifically incorporated by reference.
Preparation of compounds of the formula IVB will generally require the indanolic hydroxy groups to be protected with conventional hydroxy protecting groups prior to esterification or alkylation of the 3 and/or 4 hydroxy groups of the alkyl backbone of the mother compound. On the other hand, the differential reactivity of the indanolic hydroxy groups means that the compounds of the formula IVC can generally be prepared without corresponding protection of the 3 and 4 hydroxy groups.
Preparation of compounds of the formula IVA and IVB may require relatively stringent esterfication/alkylation conditions, thus favouring, for instance, esterification with haloactivated Lxe2x80x94Ry groups, as described above, rather than the use of a coupling agent.
A further usefull group of compounds for applying the compounds of the invention are the phenolic hydroxy compounds of the PETT series of NNRTI disclosed in WO 93/03022, WO95/06034 and PCT/SE99/00053, the contents of which are incorporated by reference. Favoured ring hydroxy compounds of this class have the formula P1: 
where one of Rp1-3 is hydroxy and the others are hydrogen, halo, C1-6 alkanoyl, C1-6 alkyl, C1-6 alkoxy etc as defined in WO95/06034, Rp4 and Rp5 are hydrogen or join to form a cis-cyclopropyl or cyclobutyl group, Rp6 is O or S and Rp7 is halo, cyano, amino etc as defined in WO95/06034. Particularly preferred compounds of this class have the formula P2: 
wherein
Rp8 is halo;
Rp9 is C1-C3 alkyl;
Rp10 is halo, especially bromo or cyano.
A preferred subset of compounds within Formula P2, particularly with regard to pharmacokinetics, has Rp10 as cyano. A further favoured subset of compounds within Formula P2, particularly with regard to ease of forming prodrugs, comprise compounds wherein Rp10 is bromo.
Preferably Rp8 is chloro and more preferably fluoro. Suitable Rp9 groups include methyl, isopropyl, n-propyl and preferably ethyl.
As depicted in Formula P2, the cyclopropyl ring is in the cis configuration, allowing two enantiomers, 1S,2S and 1R,2R 
Each of these enantiomers are potent antiretrovirals, although the different enantiomers can display subtle differences in physiological properties. For instance the 1S,2S and 1R,2R enantiomers can show a different pattern of metabolism within the P450 system. The 1S,2S enantiomer of compounds wherein Rp10 is cyano is particularly preferred as it appears unique in being able to avoid key components of the P450 system. Other retroviral agents such as the HIV protease inhibitor ritonavir interact extensively with the P450 system, leading to an array of undesirable physiological responses including extensive alteration of the metabolism of other co-administered drugs. This is of particular concern with pharmaceuticals administered for a chronic infecton where patients can expect to take a number of pharmaceuticals for years, if not decades.
Preferred NNRTI mother compounds for applying the prodrugs of the invention thus include:
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea,
and the corresponding R, R enantiomers.
This aspect of the invention thus provides prodrugs of NNRTI compounds of the formula P-1, especially P-2 wherein the phenolic hydroxy function is bonded to any of the generic structures above, such as those depicted in formula IIa, IIb, IIc, IId, IIe, IIf, Id, etc. These compounds are prepared by acylation of the relevant mother compound of formula P-1 or P-2 with the activated structure IIa, IIb etc, wherein the or each R2 group is conventionally N-protected.
As the compounds of formula P2 include an electron withdrawing group on the phenol ring to which the prodrug moiety is attached it is generally preferred to avoid direct esters such as 4-valyloxybutric acid derivatives which are otherwise effective on phenols and carbocyclic ring hydroxy functions.
Thus a convenient group of prodrugs within the scope of this aspect of the invention include those of the formula P3: 
wherein
Rp8, Rp9, Rp10, R2, R4 and R4xe2x80x2 are as defined above. Typically both of R4 and R4xe2x80x2 are H.
Preferred compounds within Formula P3 include;
(1S,2S)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1R,2R)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1R,2R)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1R,2R)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1R,2R)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
and pharmaceutically acceptable salts thereof.
An alternative preferred group of prodrugs of the invention have the Formula P4: 
where Rp8, Rp9, Rp10, R4 and R4xe2x80x2 are as defined above. L and R2 define a linker group and residue of an aliphatic amino acid, such as those of Formulae IIa, IIb, IIc, IId, IIe, IIf or those depicted in Formulae Ia and Id. Typically both of R4 and R4xe2x80x2 are H.
Favoured compounds within the class described in the immediately preceding paragraph include those of the formula P5: 
where Rp8 Rp9, Rp10, R4, R4xe2x80x2 and R2 are as defined above and Alkb is C1-C6 optionally branched, optionally monounsaturated alkyl.
Favoured compounds within Formula P5 thus include:
(1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyll-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(4-(L-valyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(4-(L-isoleucyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(4(L-valyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-(2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
and the corresponding (1R,2R) enantiomers thereof.
One variant of a branched Alkb in Formula P5 can be substituted with hydroxy which in turn is esterified with a further R2, thus defining a linker of the formula IIa, as depicted in Formula P6: 
where Rp8, Rp9, Rp10, Alk, R4, R4xe2x80x2, m, n and R2 are as defined above. Preferably each occurrence of Rx and Rxxe2x80x2 is H. Particularly favoured values for Alk, m and n include: methylene:1:1 and absent:1:0 respectively.
A further favoured group of compounds has the Formula P7: 
where Rp8, Rp9, Rp 10, Alk, R4, R4xe2x80x2, m, n and R2 are as defined above or wherein the xe2x80x94( )mxe2x80x94OR2 arm is absent. Preferably each occurrence of Rx and Rxxe2x80x2 is H. Particularly favoured values for Alk, m and n include: absent:1:1, thus defining a glycerol derivative.
Where the xe2x80x94( )mxe2x80x94OR2 arm is absent to define a structure of the formula P7xe2x80x2: 
Convenient values for Alk and n include absent:1 with R4, R4 and R4xe2x80x2 as H.
Favoured compounds within Formula P-7 thus include
(1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-valyloxy-2-(oxycarbonylmethoxy)propyl)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-isoleucyloxy-2-(oxycarbonylmethoxy)propyl)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[(2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-valyloxy-2-(oxycarbonylmethoxy)propyl)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-isoleucyloxy-2-(oxycarbonylmethoxy)propyl)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-Nxe2x80x2-[2-(5-bromocyanopyridyl)]urea,
and the corresponding R,R enantiomers.
A further favoured group of compounds omit the methyloxy group immediately adjacent the ring hydroxy function of the compound of formula P1 or P2. An example of such compounds has the formula P8: 
where Rp8, Rp9, Rp10, R2, and Alkb are as defined above. Currently favoured values for Alk include methylene, ethylene, 1,1-dimethylethylene, propylene, butylene and, in the case of said xe2x80x94OR2 substitution, glycerol.
Favoured compounds within formula P-8 thus include:
(1S,2S)-N-[cis-2-(6-fluoro-2-(L-valyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(L-isoleucyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(L-valyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(L-isoleucyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(2-(L-valyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(2-(L-isoleucyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(2-(L-valyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(2-L-isoleucyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-valyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-isoleucyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-valyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-isoleucyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-valyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-isoleucyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-cyanopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-valyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
(1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-isoleucyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-Nxe2x80x2-[2-(5-bromopyridyl)]urea,
and the corresponding R, R enantiomers
As with Formula P5/P6 and P7/P7xe2x80x2, Alkb in formula P8 can comprise an additional xe2x80x94Oxe2x80x94R2 substitution to define a compound of the formula P8xe2x80x2
where each of the variables is as defined above.
This Formulae P aspect of the invention further provides pharmaceutical compositions comprising the compounds of formula and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HIV comprising administering a compound of the formula I to a subject afflicted with HIV. The invention also extends to the use of the compounds of formula I in therapy, such as in the preparation of a medicament for the treatment of HIV infections.
In treating conditions caused by HIV, the compounds of formula I are preferably administered in an amount to achieve a plasma level of the compounds of Formula P1 of around 10 to 1000 nM and more preferably 100 to 500 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation, of the order 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosage rate for a normal adult will be around 0.05 to 5 g per day, preferably 0.1 to 2 g such as 500-750 mg, in one to four dosage units per day.
In keeping with the usual practice with HIV inhibitors it is advantageous to co-administer one to three additional antivirals to provide synergistic responses and to ensure complementary resistance patterns. Such additional antivirals may include AZT, ddI, ddC, D4T, 3TC, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, foscarnet, hydroxyurea, Hoechst-Bayer HBY 097, efavirenz, trovirdine, nevirapine, delaviridine, PFA, H2G, ABT 606, DMP-450, loviride, ritonavir, saquinavir, indinavir, amprenavir (Vertex VX 478), nelfinavir and the like, typically at molar ratios reflecting their respective activities and bioavailabilities. Generally such ratio will be of the order of 25:1 to 1:25, relative to the compound of formula I.
Compounds of this Formulae P aspect of the invention are typically prepared by alkylation of the corresponding mother compounds of Formula P1 or especially P2, which are prepared by conventional means, such as the methodology described in WO95/06034 or PCT/SE99/00053. In particular, the preparation of compounds of formula P-3 or P-4 generally proceeds by alkylation using conventional coupling conditions of a compound of the formula P-2 with the corresponding intermediate: 
where Rx and L are as defined above and R2* is R2 as defined, but N-protected with a conventional N-protecting group. Preferably the halogen activating group is iodo, which is in turn prepared by iodination of the corresponding chloro analogue. Typical coupling conditions include treatment with a base in an organic solvent such as prior to addition of the halogenated intermediate followed by conventional deprotection of the R2N-protecting group.
Compounds of formula P-8 are generally prepared by esterification of a compound of the formula P-2 with an intermediate of the formula: 
where Alkb* is a functionalised Alkb as described above, for example chloromethyl chloroformate, in an organic solvent, followed by iodination of the terminal chloro with NaI (or other activation of the functionalising group) and reaction with an N-protected R2.
The compounds of the invention can form salts which form an additional aspect of the invention. Appropriate pharmaceutically acceptable salts of the compounds of Formula I include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, furmarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. The compounds of the invention I may be isolated as the hydrate.
While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers or excipients and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of Formula I or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of pharmaceutical formulations involves intimate mixing of pharmaceutical excipients and the active ingredient in salt form, then it is often preferred to use excipients which are non-basic in nature, i.e. either acidic or neutral.
Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
With regard to compositions for oral administration (e.g. tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium caxboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, stearic acid, glycerol stearate, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
A still further aspect of the invention provides novel R2 bearing linkers suitable for derivatisation to free functions on a Drug. Preferred linkers in accordance with this aspect of the invention include compounds of the Formulae IVa: 
where R2, A, Axe2x80x2, n, m, Q, Alk, k and T are as defined above and R4 is hydroxy or an activating group such as an acid derivatives including the acid halide, such as the chloride, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinamide derived esters, N-hydroxyphthalimide derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like. Compounds of Formula IVa will be particularly useful for Drugs bearing hydroxy or amine functions.
Further preferred linkers in accordance with this aspect of the invention include compounds of the formulae IVe: 
where R2, A, Axe2x80x2, n, m, Q, Alk and T are as defined above, and R4 an activating group such as a halide, including bromo, chloro and iodo. Compounds of Formula IVe will be especially useful for Drugs bearing carboxy functions (especially those where T is O, R3 is Me and R3xe2x80x2 is H) or phosphonyl functions (especially those where T is a bond, R3 is isopropyl and R3xe2x80x2 is H).
Alternative preferred di- or trifunctional linker compounds of this aspect of the invention include compounds of the Formulae IIIa: 
where R2, A, Axe2x80x2, n, m, Q and Alk are as defined above and R4 is hydroxy or an activating moiety such as halo, including chloro, iodo and bromo.
In practice linker compounds of Formula IVa or the corresponding derivative of Formula IIxe2x80x2a will be esterified to hydroxy-bearing Drugs using conventional acylation techniques. The activated moiety of Formula IV may be preformed or generated in situ by the use of reagents such as dicyclohexylcarbodiimide (DCC) or O-(1H-benzotriazol-1-yl) N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TBTU). When an acid halide, such as the acid chloride is used, a tertiary amine catalyst, such as triethylamine, N,Nxe2x80x2-dimethylaniline, pyridine or dimethylaminopyridine may be added to the reaction mixture to bind the liberated hydrohalic acid.
The reactions are preferably carried out in an unreactive solvent such as N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or a halogenated hydrocarbon, such as dichloromethane. If desired, any of the above mentioned tertiary amine catalysts may be used as solvent, taking care that a suitable excess is present. The reaction temperature can typically be varied between xe2x88x9220xc2x0 C. and 60xc2x0 C., but will preferably be kept between 5xc2x0 and 50xc2x0 C. After a period of 1 to 60 hours the reaction will usually be essentially complete. The progress of the reaction can be followed using thin layer chromatography (TLC) and appropriate solvent systems. In general, when the reaction is completed as determined by TLC, the product is extracted with an organic solvent and purified by chromatography and/or recrystallisation from an appropriate solvent system.
By-products where acylation has taken place on an inappropriate function can be separated by chromatography, but such misacylation can be minimized by controlled reaction conditions. These controlled conditions can be achieved, for example, by manipulating the reagent concentrations or rate of addition, especially of the acylating agent, by lowering the temperature or by the choice of solvent. The reaction can be followed by TLC to monitor the controlled conditions. It may additionally or alternatively be convenient to protect exposed hydroxy and other functions on the Drug with conventional protecting groups to forestall misacylation.
Linkers of Formula IVa or the corresponding derivatives of Formula IIxe2x80x2a may alternatively be amide bonded to free primary or secondary amine functions on the Drug using conventional chemistry in the peptide art.
Linkers of Formula IIIa or IVd or the corresponding derivatives of Formula IIIxe2x80x2 and IIxe2x80x2d will generally be acylated to free carboxyl functions on the Drug in an analogous, but reversed fashion to the above described acylation of Drugs with hydroxy functions. U.S. Pat. No. 4,486,425 which is incorporated by reference illustrates a convenient process.
Linkers of Formula IVa wherein V comprises a structure of the formula IIc can be prepared by a by a two stage process. In particular a compound of the formula ClC(xe2x95x90O)OC(R4)(R4xe2x80x2)Cl can be reacted with a suitable accessible hydroxy function on the Drug (optionally protected on other functions with conventional protecting groups) as is known in the cephalosporin art. The resulting Drug-Oxe2x80x94C(xe2x95x90O)OC(R4)(R4xe2x80x2)chloride is then reacted with an R2 bearing linker wherein a free function comprises a carboxyl function, such as the potassium salt.
Linkers of Formula IVe or the corresponding derivatives of Formula IIe can be esterified to phosphonyl and phosphoryl functions of Drugs analogously to the processes shown in U.S. Pat. Nos. 4,337,201 and 5,227,506, which are incorporated by reference. Corresponding methodology is applicable when R2, is esterified to a phosphonyl or phosphoryl group via a spacer of the Formula IIb as defined above.
The preparation of further linker groups and their application to Drugs is shown in the following Examples.
As the Drugs envisaged in the use of the present invention are proven pharmaceuticals, the starting materials for preparing the prodrugs of the invention are either available in commerce or are extensively described in the medical literature, including the FDA and other registration files for the respective drugs.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (John Wiley and Sons, New York, 1981), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1, xcex1-dinethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Favoured N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).
Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsiyl, triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like, substituted ethyl ethers such as 1-ethoxymethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such as trityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especially the chloride). Ester hydroxy protecting groups include esters such as formate, benzylformate, chlioroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like. xe2x80x9cOptional substituentsxe2x80x9d can include hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6alkyl, C1-C6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro, and the like. xe2x80x9cRingxe2x80x9d as used herein includes atoms including monocyclic rings such as furyl, thienyl, pyranyol, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like or bicyclic rings especially of the above fused to a phenyl ring such as indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothienyl etc. The carbo or heterocyclic ring may be bonded via a carbon to the remainder of the linker via a hetero atom, typically a nitrogen atom, such as N-piperidyl, N-morpholinyl etc.